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e5 HISTORICAL INTRODUCTION required to operate on real patients, or on soldiers injured at Sebastopol or some other battlefield. The book they planned together was a practi - cal one, designed to encourage youngsters to study anatomy, help them pass exams, and assist them as budding surgeons. It was not simply an anatomy textbook, but a guide to dissecting procedure, and to the major operations. Gray and Carter belonged to a generation of anatomists ready to infuse the study of human anatomy with a new, and respectable, scien - tificity. Disreputable aspects of the profession’s history, acquired during the days of body-snatching, were assiduously being forgotten. The Anatomy Act of 1832 had legalized the requisition of unclaimed bodies from workhouse and hospital mortuaries, and the study of anatomy (now with its own Inspectorate) was rising in respectability in Britain. The private anatomy schools that had flourished in the Regency period were closing their doors, and the major teaching hospitals were erecting new, purpose-built dissection rooms (Richardson 2000). The best-known student works when Gray and Carter had qualified were probably Erasmus Wilson’s Anatomist’s Vade Mecum , and Elements of Anatomy by Jones Quain. Both works were small – pocket-sized – but Quain came in two thick volumes. Both Quain’s and Wilson’s works were good books in their way, but their small pages of dense type, and even smaller illustrations, were somewhat daunting, seeming to demand much nose-to-the-grindstone effort from the reader. The planned new textbook’s dimensions and character were serious matters. Pocket manuals were commercially successful because they appealed to students by offering much knowledge in a small compass. But pocket-sized books had button-sized illustrations. Knox’s Manual of Human Anatomy, for example, was a good book, but was only 6 inches by 4 (15 × 10 cm) and few of its illustrations occupied more than one- third of a page. Gray and Carter must have discussed this matter between themselves, and with Gray’s publisher, JW Parker & Son, before deci- sions were taken about the size and girth of the new book, and espe - cially the size of its illustrations. While Gray and Carter were working on the book, a new edition of Quain’s was published; this time it was a ‘triple-decker’ – in three volumes – of 1740 pages in all. The two men were earnestly engaged for the following 18 months in work for the new book. Gray wrote the text, and Carter created the illustrations; all the dissections were undertaken jointly. Their working days were long – all the hours of daylight, eight or nine hours at a stretch – right through 1856, and well into 1857. We can infer from the warmth of Gray’s appreciation of Carter in his published acknowledge- ments that their collaboration was a happy one. The Author gratefully acknowledges the great services he has derived in the execution of this work, from the assistance of his friend, Dr. H. V. Carter, late Demonstrator of Anatomy at St George’s Hospital. All the drawings from which the engravings were made, were executed by him. (Gray 1858) With all the dissections done, and Carter’s inscribed wood-blocks at the engravers, Gray took six months’ leave from his teaching at St George’s to work as a personal doctor for a wealthy family. It was probably as good a way as any to get a well-earned break from the dissecting room and the dead-house (Nicol 2002). Carter sat the examination for medical officers in the East India Company, and sailed for India in the spring of 1858, when the book was still in its proof stages. Gray had left a trusted colleague, Timothy Holmes, to see it through the press. Holmes’s association with the first edition would later prove vital to its survival. Gray looked over the final galley proofs, just before the book finally went to press. THE FIRST EDITION The book Gray and Carter had created together, Anatomy, Descriptive and Surgical, appeared at the very end of August 1858, to immediate Gray’s Anatomy is now on its way to being 160 years old. The book is a rarity in textbook publishing in having been in continuous publication on both sides of the Atlantic Ocean, since 1858. One and a half centu - ries is an exceptionally long era for a textbook. Of course, the volume now is very different from the one Mr Henry Gray first created with his colleague Dr Henry Vandyke Carter, in mid-Victorian London. In this introductory essay, I shall explain the long history of Gray’s, from those Victorian days right up to today. The shortcomings of existing anatomical textbooks probably impressed themselves on Henry Gray when he was still a student at St George’s Hospital Medical School, near London’s Hyde Park Corner, in the early 1840s. He began thinking about creating a new anatomy textbook a decade later, while war was being fought in the Crimea. New legislation was being planned that would establish the General Medical Council (1858) to regulate professional education and standards. Gray was twenty-eight years old, and a teacher himself at St George’s. He was very able, hard-working and highly ambitious, already a Fellow of the Royal Society, and of the Royal College of Surgeons. Although little is known about his personal life, his was a glittering career so far, achieved while he served and taught on the hospital wards and in the dissecting room (Fig. 1) (Anon 1908). Gray shared the idea for the new book with a talented colleague on the teaching staff at St George’s, Henry Vandyke Carter, in November 1855. Carter was from a family of Scarborough artists, and was himself a clever artist and microscopist. He had produced fine illustrations for Gray’s scientific publications before, but could see that this idea was a much more complex project. Carter recorded in his diary: Little to record. Gray made proposal to assist by drawings in bringing out a Manual for students: a good idea but did not come to any plan … too exacting, for would not be a simple artist (Carter 1855). Neither of these young men was interested in producing a pretty book, or an expensive one. Their purpose was to supply an affordable, accurate teaching aid for people like their own students, who might soon be Fig. 1 Henry Gray (1827–1861) is shown here in the foreground, seated by the feet of the cadaver. The photograph was taken by a medical student, Joseph Langhorn. The room is the dissecting room of St George’s Hospital Medical School in Kinnerton Street, London. Gray is shown surrounded by staff and students. When the photo was taken, on 27 March 1860, Carter had left St George’s, to become Professor of Anatomy and Physiology at Grant Medical College, in Bombay (nowadays Mumbai). The second edition of Gray’s Anatomy was in its proof stages, to appear in December 1860. Gray died just over a year later, in June 1861, at the height of his powers.

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Historical introduction e6Fig. 2 Henry Vandyke Carter (1831–1897). Carter was appointed Honorary Surgeon to Queen Victoria in 1890. acclaim. Reviews in The Lancet and the British Medical Journal were highly complimentary, and students flocked to buy. It is not difficult to understand why it was a runaway success. Gray’s Anatomy knocked its competitors into a cocked hat. It was considerably smaller and more slender than the doorstopper with which modern readers are familiar. The book held well in the hand, it felt substantial, and it contained everything required. To contemporaries, it was small enough to be portable, but large enough for decent illustrations: ‘royal octavo’ – 912 × 6 inches (24 × 15 cm) – about two-thirds of modern A4 size. Its medium-size, single-volume format was far removed from Quain, yet double the size of Knox’s Manual. Simply organized and well designed, the book explains itself confi - dently and well; the clarity and authority of the prose are manifest. But what made it unique for its day was the outstanding size and quality of the illustrations. Gray thanked the wood engravers Butterworth and Heath for the ‘great care and fidelity’ they had displayed in the engrav- ings, but it was really to Carter that the book owed its extraordinary success. The beauty of Carter’s illustrations resides in their diagrammatic clarity, quite atypical for their time. The images in contemporary anatomy books were usually ‘proxy-labelled’: dotted with tiny numbers or letters (often hard to find or read) or bristling with a sheaf of num - bered arrows, referring to a key situated elsewhere, usually in a footnote, which was sometimes so lengthy it wrapped round on to the following page. Proxy labels require the reader’s eye to move to and fro: from the structure to the proxy label to the legend and back again. There was plenty of scope for slippage, annoyance and distraction. Carter’s illustra - tions, by contrast, unify name and structure, enabling the eye to assimi - late both at a glance. We are so familiar with Carter’s images that it is hard to appreciate how incredibly modern they must have seemed in 1858. The volume made human anatomy look new, exciting, accessible and do-able. The first edition was covered in a brown bookbinder’s cloth embossed all over in a dotted pattern, and with a double picture-frame border. Its spine was lettered in gold blocking: sense of calamity. The grand old medical man Sir Benjamin Brodie, Sergeant-Surgeon to the Queen, and the great supporter of Gray to whom Anatomy had been dedicated, cried forlornly: ‘Who is there to take his place?’ (Anon 1908). But old JW Parker ensured the survival of Gray’s by inviting Timothy Holmes, the doctor who had helped proof-read the first edition, and who had filled Gray’s shoes at the medical school, to serve as Editor for the next edition. Other long-running anatomy works, such as Quain, remained in print in a similar way, co-edited by other hands (Quain 1856). Holmes (1825–1907) was another gifted St George’s man, a scholar - ship boy who had won an exhibition to Cambridge, where his brilliance was recognized. Holmes was a Fellow of the Royal College of Surgeons at 28. John Parker junior had commissioned him to edit A System of Surgery (1860–64), an important essay series by distinguished surgeons on subjects of their own choosing. Many of Holmes’s authors remain important figures, even today: John Simon, James Paget, Henry Gray, Ernest Hart, Jonathan Hutchinson, Brown-Séquard and Joseph Lister. Holmes had lost an eye in an operative accident, and he had a gruff manner that terrified students, yet he published a lament for young Parker that reveals him capable of deep feeling (Holmes 1860). John Parker senior’s heart, however, was no longer in publishing. His son’s death had closed down the future for him. The business, with all its stocks and copyrights, was sold to Messrs Longman. Parker retired to the village of Farnham, where he later died. With Holmes as editor, and Longman as publisher, the immediate future of Gray’s Anatomy was assured. The third edition appeared in 1864 with relatively few changes, Gray’s estate receiving the balance of his royalty after Holmes was paid £100 for his work. THE MISSING OBITUARY Why no obituary appeared for Henry Gray in Gray’s Anatomy is curious. Gray had referred to Holmes as his ‘friend’ in the preface to the first edition, yet it would also be true to say that they were rivals. Both had just applied for a vacant post at St George’s, as Assistant Surgeon. Had Gray lived, it is thought that Holmes may not have been appointed, despite his seniority in age (Anon 1908). Later commentators have suggested, as though from inside knowl - edge, that Holmes’s ‘proof-reading’ included improving Gray’s writing … with ‘DESCRIPTIVE AND SURGICAL’ in small capitals underneath. Gray’s Anatomy is how it has been referred to ever since. Carter was given credit with Gray on the book’s title page for undertaking all the dissec - tions on which the book was based, and sole credit for all the illustra - tions, though his name appeared in a significantly smaller type, and he was described as the ‘Late Demonstrator in Anatomy at St George’s Hospital’ rather than being given his full current title, which was Profes - sor of Anatomy and Physiology at Grant Medical College, Bombay. Gray was still only a Lecturer at St George’s and he may have been aware that his words had been upstaged by the quality of Carter’s anatomical images. He need not have worried: Gray is the famous name on the spine of the book. Gray was paid £150 for every thousand copies sold. Carter never received a royalty payment, just a one-off fee at publication, which may have allowed him to purchase the long-wished-for microscope he took with him to India (Fig. 2). The first edition print-run of 2000 copies sold out swiftly. A parallel edition was published in the United States in 1859, and Gray must have been deeply gratified to have to revise an enlarged new English edition in 1859–60, though he was surely saddened and worried by the death of his publisher, John Parker junior, at the young age of 40, while the book was going through the press. The second edition came out in the December of 1860 and it too sold like hot cakes, as indeed has every subsequent edition. The following summer, in June 1861, at the height of his powers and full of promise, Henry Gray died unexpectedly at the age of only 34. Gray had contracted smallpox while nursing his nephew. A new strain of the disease was more virulent than the one with which Gray had been vaccinated as a child; the disease became confluent, and Gray died in a matter of days. Within months, the whole country would be pitched into mourning for the death of Prince Albert. The creative era over which he had pre - sided – especially the decade that had flowered since the Great Exhibi - tion of 1851 – would be history. THE BOOK SURVIVES Anatomy Descriptive and Surgical could have died too. With Carter in India, the death of Gray, so swiftly after that of the younger Parker, might have spelled catastrophe. Certainly, at St George’s there was a GRAY’S ANATOMY

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Historical introduction e7 were not as yet perfected, and in any case could not provide the bold simplicity of line required for a book like Gray’s, which depended so heavily on clear illustration and clear lettering. Recognizing the inferior - ity of half-tone illustrations by comparison with Carter’s wood-engraved originals, Pick and Howden courageously decided to jettison the second-rate half-tones altogether. Most of the next edition’s illustrations were either Carter’s, or old supplementary illustrations inspired by his work, or newly commissioned wood engravings or line drawings, intended ‘to harmonize with Carter’s original figures’ . They successfully emulated Carter’s verve. Having fewer pages and lighter paper, the 1905 (sixteenth edition) weighed less than its predecessor, at 4 lb 1 1 oz/2.1 kg. Typographically, the new edition was superb. Howden took over as sole editor in 1909 (seventeenth edition) and immediately stamped his personality on Gray’s. He excised ‘Surgical’ from the title, changing it to Anatomy Descriptive and Applied, and removed Carter’s name altogether. He also instigated the beginnings of an editorial board of experts for Gray’s, by adding to the title page ‘Notes on Applied Anatomy’ by AJ Jex-Blake and W Fedde Fedden, both St George’s men. For the first time, the number of illustrations exceeded one thousand. Howden was responsible for the significant innovation of a short historical note on Henry Gray himself, nearly 60 years after his death, which included a portrait photograph (1918, twentieth edition). THE NOMENCLATURE CONTROVERSY Howden’s era, and that of his successor TB Johnston (of Guy’s), was overshadowed by a cloud of international controversy concerning ana - tomical terminology. European anatomists were endeavouring to stand - ardize anatomical terms, often using Latinate constructions, a move resisted in Britain and the United States. Gray’s became mired in these debates for over 20 years. The attempt to be fair to all sides by using multiple terms doubtless generated much confusion amongst students, until a working compromise was at last arrived at in 1955 (thirty-second edition, 1958). Johnston oversaw the second retitling of the book (in 1938, twenty- seventh edition): it was now, officially, Gray’s Anatomy, finally ending the fiction that it had ever been known as anything else. Gray’s suffered from paper shortages and printing difficulties in World War II, but suc - cessive editions nevertheless continued to grow in size and weight, while illustrations were replaced and added as the text was revised. Between Howden’s first sole effort (1909, seventeenth edition) and Johnston’s last edition (1958, thirty-second edition), Gray’s expanded by over 300 pages – from 1296 to 1604 pages, and almost 300 addi - tional illustrations brought the total to over 1300. Johnston also intro - duced X-ray plates (1938) and, in 1958 (thirty-second edition), electron micrographs by AS Fitton-Jackson, one of the first occasions on which a woman was credited with a contribution to Gray’s. Johnston felt com - pelled to mention that she was ‘a blood relative of Henry Gray himself’, perhaps by way of mitigation. AFTER WORLD WAR II The editions of Gray’s issued in the decades immediately following the Second World War give the impression of intellectual stagnation. Steady expansion continued in an almost formulaic fashion, with the insertion of additional detail. The central historical importance of innovation in the success of Gray’s seems to have been lost sight of by its publishers and editors – Johnston (1930–1958, twenty-fourth to thirty-second editions), J Whillis (co-editor with Johnston, 1938–1954), DV Davies (1958–1967, thirty-second to thirty-fourth editions) and F Davies (co-editor with DV Davies 1958–1962, thirty-second to thirty-third editions). Gray’s had become so pre-eminent that perhaps complacency crept in, or editors were too daunted or too busy to confront the ‘massive undertaking’ of a root and branch revision (Tansey 1995). The unexpected deaths of three major figures associated with Gray’s in this era, James Whillis, Francis Davies and David Vaughan Davies – each of whom had been ready to take the editorial reins – may have contributed to retarding the process. The work became somewhat dull. KEY EDITION: 1973 DV Davies had recognized the need for modernization, but his unex - pected death left the work to other hands. Two Professors of Anatomy at Guy’s, Roger Warwick and Peter Williams, the latter of whom had been involved as an indexer for Gray’s for several years, regarded it as an honour to fulfill Davies’s intentions. Their thirty-fifth edition of 1973 was a significant departure from tradition. Over 780 pages (of 1471) were newly written, almost a third style. This could be a reflection of Holmes’s own self-regard, but there may be some truth in it. There can be no doubt that, as Editor of seven subsequent editions of Gray’s Anatomy (third to ninth editions, 1864– 1880), Holmes added new material, and had to correct and compress passages, but it is also possible that, back in 1857, Gray’s original manuscript had been left in a poor state for Holmes to sort out. In other works, Gray’s writing style was lucid, but he always seems to have paid a copyist to transcribe his work prior to submission. The original manu - script of Gray’s Anatomy, sadly, has not survived, so it is impossible to be sure how much of the finished version had actually been written by Holmes. It may be that Gray’s glittering career, or perhaps the patronage that unquestionably advanced it, created jealousies among his colleagues, or that there was something in Gray’s manner that precluded affection, or that created resentments among clever social inferiors like Carter and Holmes, especially if they felt their contributions to his brilliant career were not given adequate credit. Whatever the explanation, no reference to Gray’s life or death appeared in Gray’s Anatomy itself until the twen - tieth century (Howden et al 1918). A SUCCESSION OF EDITORS Holmes expanded areas of the book that Gray himself had developed in the second edition (1860), notably in ‘general’ anatomy (histology) and ‘development’ (embryology). In Holmes’s time as Editor, the volume grew from 788 pages in 1864 to 960 in 1880 (ninth edition), with the histological section paginated separately in roman numerals at the front of the book. Extra illustrations were added, mainly from other published sources. The connections with Gray and Carter, and with St George’s, were maintained with the appointment of the next editor, T. Pickering Pick, who had been a student at St George’s in Gray’s time. From 1883 (tenth edition) onwards, Pick kept up with current research, rewrote and inte - grated the histology and embryology into the volume, dropped Holmes from the title page, removed Gray’s preface to the first edition, and added bold subheadings, which certainly improved the appearance and accessibility of the text. Pick said he had ‘tried to keep before himself the fact that the work is intended for students of anatomy rather than for the Scientific Anatomist’ (thirteenth edition, 1893). Pick also introduced colour printing (in 1887, eleventh edition) and experimented with the addition of illustrations using the new printing method of half-tone dots: for colour (which worked) and for new black- and-white illustrations (which did not). Half-tone shades of grey com - pared poorly with Carter’s wood engravings, still sharp and clear by comparison. What Henry Vandyke Carter made of these changes is a rich topic for speculation. He returned to England in 1888, having retired from the Indian Medical Service, full of honours – Deputy Surgeon General, and in 1890, he was made Honorary Surgeon to Queen Victoria. Carter had continued researching throughout his clinical medical career in India, and became one of India’s foremost bacteriologists/tropical disease specialists before there was really a name for either discipline. Carter made some important discoveries, including the fungal cause of mycetoma, which he described and named. He was also a key figure in confirming scientifically in India some major international discoveries, such as Hansen’s discovery of the cause of leprosy, Koch’s discovery of the organism causing tuberculosis, and Laveran’s discovery of the organ - ism that causes malaria. Carter married late in life, and his wife was left with two young children when he died in Scarborough in 1897, aged 65. Like Gray, he received no obituary in the book. When Pick was joined on the title page by Robert Howden (a profes - sional anatomist from the University of Durham) in 1901 (fifteenth edition), the volume was still easily recognizable as the book Gray and Carter had created. Although many of Carter’s illustrations had been revised or replaced, many others still remained. Sadly, though, an entire section (embryology) was again separately paginated, as its revision had taken longer than anticipated. Gray’s had grown, seemingly inexorably, and was now quite thick and heavy: 1244 pages, weighing 5 lb 8 oz/2.5 kg. Both co-editors, and perhaps also its publisher, were dis - satisfied with it. KEY EDITION: 1905 Serious decisions were taken well in advance of the next edition, which turned out to be Pick’s last with Howden. Published 50 years after Gray had first suggested the idea to Carter, the 1905 (sixteenth) edition was a landmark one. The period 1880–1930 was a difficult time for anatomical illustra- tion, because the new techniques of photo-lithography and half-tone

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Historical introduction e8had developed a distinct character of its own in the interval), and sold extremely well there (Williams and Warwick 1973). The influence of the Warwick and Williams edition was forceful and long-lasting, and set a new pattern for the following quarter-century. As has transpired several times before, wittingly or unwittingly, a new editor was being prepared for the future: Dr Susan Standring (of Guy’s), who created the new bibliography for the 1973 edition of Gray’s, went on to serve on the editorial board, and has served as Editor-in-Chief for the last two editions before this one (2005–2008, thirty-ninth and fortieth editions). Both editions are important for dif - ferent reasons. For the thirty-ninth edition, the entire content of Gray’s was reorgan- ized, from systematic to regional anatomy. This great sea-change was not just organizational but historic, because, since its outset, Gray’s had prioritized bodily systems, with subsidiary emphasis on how the systems interweave in the regions of the body. Professor Standring explained that this regional change of emphasis had long been asked for by readers and users of Gray’s, and that new imaging techniques in our era have raised the clinical importance of local anatomy (Standring 2005). The change was facilitated by an enormous collective effort on the part of the editorial team and the illustrators. The subsequent and current editions consolidate that momentous change. (See Table 1.) Table 1  Gray’s Anatomy  Editions Edition Date Author/Editor(s) Publisher Title 1st 1858 Henry Gray JW Parker & Son Anatomy Descriptive and Surgical The drawings by Henry Vandyke Carter. The dissections jointly by the author and Dr Carter 2nd 1860 Henry Gray JW Parker & Son 3rd 1864 T Holmes Longman 4th 1866 T Holmes Longman 5th 1869 T Holmes Longman 6th 1872 T Holmes Longman 7th 1875 T Holmes Longman 8th 1877 T Holmes Longman 9th 1880 T Holmes Longman 10th 1883 TP Pick Longman 11th 1887 TP Pick Longman 12th 1890 TP Pick Longman 13th 1893 TP Pick Longman Gray’s preface removed 14th 1897 TP Pick Longman 15th 1901 TP Pick & R Howden Longman 16th 1905 TP Pick & R Howden Longman 17th 1909 Robert Howden Longman Anatomy Descriptive and Applied Notes on applied anatomy by AJ Jex-Blake & W Fedde Fedden 18th 1913 Robert Howden & Blake & Fedden Longman 19th 1916 Robert Howden & Blake & Fedden Longman 20th 1918 Robert Howden & Blake & Fedden Longman First edition ever to feature a photograph and obituary of Henry Gray 21st 1920 Robert Howden Longman Notes on applied anatomy by AJ Jex-Blake & John Clay 22nd 1923 Robert Howden Longman Notes on applied anatomy by John Clay & John D Lickley 23rd 1926 Robert Howden Longman 24th 1930 TB Johnston Longman 25th 1932 TB Johnston Longman 26th 1935 TB Johnston Longman 27th 1938 TB Johnston & J Whillis Longman Gray’s Anatomy 28th 1942 TB Johnston & J Whillis Longman 29th 1946 TB Johnston & J Whillis Longman 30th 1949 TB Johnston & J Whillis Longman 31st 1954 TB Johnston & J Whillis Longman 32nd 1958 TB Johnston & DV Davies & F Davies Longman 33rd 1962 DV Davies & F Davies Longman 34th 1967 DV Davies & RE Coupland Longman 35th 1973 Peter L Williams & Roger Warwick Longman With a separate volume: Functional Neuroanatomy of Man – being the neurology section of Gray’s Anatomy. 35th edition, 1975 36th 1980 Roger Warwick & Peter L Williams Churchill Livingstone 37th 1989 Peter L Williams Churchill Livingstone 38th 1995 Peter L Williams & Editorial Board Churchill Livingstone 39th 2005 Susan Standring & Editorial Board Elsevier The Anatomical Basis of Clinical Practice 40th 2008 Susan Standring & Editorial Board Elsevier The Anatomical Basis of Clinical Practice 41st 2015 Susan Standring & Editorial Board Elsevier The Anatomical Basis of Clinical Practiceof the illustrations were newly commissioned, and the illustration cap - tions were freshly written throughout. With a complete re-typesetting of the text in larger double-column pages, a new index and the innova - tion of a bibliography, this edition of Gray’s looked and felt quite unlike its 1967 (thirty-fourth edition) predecessor, and much more like its modern incarnation. This 1973 edition departed from earlier volumes in other significant ways. The editors made explicit their intention to try to counter the impetus towards specialization and compartmentalization in twentieth- century medicine, by embracing and attempting to reintegrate the com - plexity of the available knowledge. Warwick and Williams openly renounced the pose of omniscience adopted by many textbooks, believ - ing it important to accept and mention areas of ignorance or uncer - tainty. They shared with the reader the difficulty of keeping abreast in the sea of research, and accepted with a refreshing humility the impos- sibility of fulfilling their own ambitious programme. Warwick and Williams’s 1973 edition had much in common with Gray and Carter’s first edition. It was bold and innovative – respectful of its heritage, while also striking out into new territory. It was visually attractive and visually informative. It embodied a sense of a treasury of information laid out for the reader (Williams and Warwick 1973). It was published simultaneously in the United States (the American Gray’s

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Historical introduction e9 Howden R, Jex-Blake AJ, Fedde Fedden W (eds) 1918 Gray’s Anatomy, 20th ed. London: Longman. Lewis H Sinclair 1925 Arrowsmith. New York: Harcourt Brace; p. 4. Nicol KE 2002 Henry Gray of St George’s Hospital: a Chronology. London: published by the author. Quain J 1856 Elements of Anatomy. Ed. by Sharpey W, Ellis GV. London: Walton & Maberly. Richardson R 2000 Death, Dissection and the Destitute. Chicago: Chicago University Press; pp. 193–249, 287, 357. Richardson R 2008 The Making of Mr Gray’s Anatomy. Oxford: Oxford University Press. Standring S (ed.) 2005 Preface. In: Gray’s Anatomy, 39th ed. Elsevier: London. Tansey EM 1995 A brief history of Gray’s Anatomy. In: Gray’s Anatomy, 38th ed. London: Churchill Livingstone. Williams PL, Warwick R (eds.) 1973 Preface. In: Gray’s Anatomy, 35th ed. London: Churchill Livingstone.THE DOCTORS’ BIBLE Neither Gray nor Carter, the young men who – by their committed hard work between 1856 and 1858 – created the original Gray’s Anatomy, would have conceived that so many years after their deaths their book would not only be a household name, but also be regarded as a work of such pre-eminent importance that a novelist half a world away would rank it as cardinal – alongside the Bible and Shakespeare – to a doctor’s education (Sinclair Lewis 1925, Richardson 2008). From this forty-first edition of Gray’s Anatomy, we can look back to appraise the long-term value of their efforts. We can discern how the book they created tri - umphed over its competitors, and has survived pre-eminent. Gray’s is a remarkable publishing phenomenon. Although the volume now looks quite different to the original, and contains so much more, its kinship with the Gray’s Anatomy of 1858 is easily demonstrable by direct descent, every edition updated by Henry Gray’s successor. Works are rare indeed that have had such a long history of continuous publication on both sides of the Atlantic, and such a useful one. Ruth Richardson, MA, DPhil, FRHistS Senior Visiting Research Fellow, Centre for Life-Writing Research, King’s College London; Affiliated Scholar in the History and Philosophy of Science, University of Cambridge, UK REFERENCES Anon 1908 Henry Gray. St George’s Hospital Gazette 16:49–54. Carter HV 1855 Diary. Wellcome Western Manuscript 5818; 25 Nov.Gray H 1858 Preface. In: Anatomy: Descriptive and Surgical. London: JW Parker & Son. Holmes T (ed.) 1860 I: Preface. In: A System of Surgery. London: JW Parker & Son.ACKNOWLEDGEMENTS For their assistance while I was undertaking the research for this essay, I should like to thank the Librarians and Archivists and Staff at the British Library, Society of Apothecaries, London School of Hygiene and Tropical Medicine, Royal College of Surgeons, Royal Society of Medi - cine, St Bride Printing Library, St George’s Hospital Tooting, Scarbor - ough City Museum and Art Gallery, University of Reading, Wellcome Institute Library, Westminster City Archives and Windsor Castle; and the following individuals: Anne Bayliss, Gordon Bell, David Buchanan, Dee Cook, Arthur Credland, Chris Hamlin, Victoria Killick, Louise King, Keith Nicol, Sarah Potts, Mark Smalley, and Nallini Thevakarrunai. Above all, my thanks to Brian Hurwitz, who has read and advised on the evolving text.

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xviANATOMICAL NOMENCLATURE with the median plane; although often employed, ‘parasagittal’ is there - fore redundant and should not be used. The coronal (frontal) plane is orthogonal to the median plane and divides the body into anterior (front) and posterior (back). The horizontal (transverse) plane is orthogonal to both median and sagittal planes. Radiologists refer to transverse planes as (trans)axial; convention dictates that axial anatomy is viewed as though looking from the feet towards the head. Structures nearer the head are superior, cranial or (sometimes) cephalic (cephalad), whereas structures closer to the feet are inferior; caudal is most often used in embryology to refer to the hind end of the embryo. Medial and lateral indicate closeness to the median plane, medial being closer than lateral; in the anatomical position, the little finger is medial to the thumb, and the great toe is medial to the little toe. Specialized terms may also be used to indicate medial and lateral. Thus, in the upper limb, ulnar and radial are used to mean medial and lateral, respectively; in the lower limb, tibial and fibular (peroneal) are used to mean medial and lateral, respectively. Terms may be based on embryological relationships; the border of the upper limb that includes the thumb, and the border of the lower limb that includes the great toe are the pre-axial borders, whilst the opposite borders are the post-axial borders. Various degrees of obliquity are acknowledged using com- pound terms, e.g. posterolateral. When referring to structures in the trunk and upper limb, we have freely used the synonyms anterior, ventral, flexor, palmar and volar, and posterior, dorsal and extensor. We recognize that these synonyms are not always satisfactory, e.g. the extensor aspect of the leg is anterior with respect to the knee and ankle joints, and superior in the foot and digits; the plantar (flexor) aspect of the foot is inferior. Dorsal (dorsum) and ventral are terms used particularly by embryologists and neuroanato - mists; they therefore feature most often in Sections 2 and 3. Distal and proximal are used particularly to describe structures in the limbs, taking the datum point as the attachment of the limb to the trunk (sometimes referred to as the root), such that a proximal structure is closer to the attachment of the limb than a distal structure. However, proximal and distal are also used in describing branching structures, e.g. bronchi, vessels and nerves. External (outer) and internal (inner) refer to the distance from the centre of an organ or cavity, e.g. the layers of the body wall, or the cortex and medulla of the kidney. Superficial and deep are used to describe the relationships between adjacent struc - tures. Ipsilateral refers to the same side (of the body, organ or structure), bilateral to both sides, and contralateral to the opposite side. Teeth are described using specific terms that indicate their relation - ship to their neighbours and to their position within the dental arch; these terms are described on page 517.Anatomy is the study of the structure of the body. Conventionally, it is divided into topographical (macroscopic or gross) anatomy (which may be further divided into regional anatomy, surface anatomy, neuro - anatomy, endoscopic and imaging anatomy); developmental anatomy (embryogenesis and subsequent organogenesis); and the anatomy of microscopic and submicroscopic structure (histology). Anatomical language is one of the fundamental languages of medi - cine. The unambiguous description of thousands of structures is impos - sible without an extensive and often highly specialized vocabulary. Ideally, these terms, which are often derived from Latin or Greek, should be used to the exclusion of any other, and eponyms should be avoided. In reality, this does not always happen. Many terms are ver - nacularized and, around the world, synonyms and eponyms still abound in the literature, in medical undergraduate classrooms and in clinics. The Terminologia Anatomica, 1 drawn up by the Federative Com- mittee on Anatomical Terminology (FCAT) in 1998, continues to serve as our reference source for the terminology for macroscopic anatomy, and the text of the forty-first edition of Gray’s Anatomy is almost entirely TA-compliant. However, where terminology is at variance with, or, more likely, is not included in, the TA, the alternative term used either is cited in the relevant consensus document or position paper, or enjoys wide - spread clinical usage. Synonyms and eponyms are given in parentheses on first usage of a preferred term and not shown thereafter in the text; an updated list of eponyms and short biographical details of the clini - cians and anatomists whose names are used in this way is available in the e-book for reference purposes (see Preface , p. ix, for further discus - sion of the use of eponyms). PLANES, DIRECTIONS AND RELATIONSHIPS To avoid ambiguity, all anatomical descriptions assume that the body is in the conventional ‘anatomical position’, i.e. standing erect and facing forwards, upper limbs by the side with the palms facing forwards, and lower limbs together with the toes facing forwards (Fig. 1). Descrip - tions are based on four imaginary planes – median, sagittal, coronal and horizontal – applied to a body in the anatomical position. The median plane passes longitudinally through the body and divides it into right and left halves. The sagittal plane is any vertical plane parallel 1Terminologia Anatomica (1998) is the joint creation of the Federative Committee on Anatomical Terminology (FCAT) and the Member Associations of the Interna - tional Federation of Associations of Anatomists (IFAA).

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AnAtomic Al nomencl Ature xvii Fig. 1 The terminology widely used in descriptive anatomy. Abbreviations shown on arrows: AD, adduction; AB, abduction; FLEX, flexion (of the thigh at the hip joint); EXT, extension (of the leg at the knee joint). LEFT LATERAL ASPECTPOSTERIOR ASPECTSUPERIOR ASPECT Lateral InversionEversionMedial (internal) rotationLateral (external) rotationPronationSupinationDistallyProximally DistallyProximallyMedial (internal) rotationLateral (external) rotationMedialPosterior or dorsalAnterior or ventralCoronal plane Median or sagittal plane Transverse or horizontal planeInferior or caudal Superior or cranial INFERIOR ASPECTANTERIOR ASPECTRIGHT LATERAL ASPECT

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xviiiBIBLIOGRAPHY OF SELECTED TITLES Haaga JR, Dogra VS, Forsting M, Gilkeson RC, Ha KH, Sundaram M 2009 CT and MR Imaging of the Whole Body, 5th ed. St Louis: Elsevier, Mosby. Lasjaunias P, Berenstein A, ter Brugge K 2001 Surgical Neuroangio­ graphy, vol 1. Clinical Vascular Anatomy and Variations, 2nd ed. Berlin, New York: Springer. Meyers MA 2000 Dynamic Radiology of the Abdomen: Normal and Pathologic Anatomy, 5th ed. New York: Springer. Pomeranz SJ 1992 MRI Total Body Atlas. Cincinnati: MRI ­EFI. Spratt JD, Salkowski LR, Weir J, Abrahams PH 2010 Imaging Atlas of Human Anatomy, 4th ed. London: Elsevier, Mosby. Sutton D, Reznek R, Murfitt J 2002 Textbook of Radiology and Imaging, 7th ed. Edinburgh: Elsevier, Churchill Livingstone. Whaites E, Drage N 2013 Essentials of Dental Radiography and Radiol ­ ogy, 5th ed. Edinburgh: Elsevier, Churchill Livingstone.Wicke L 2004 Atlas of Radiologic Anatomy, 7th ed. Philadelphia: Elsevier, WB Saunders. CLINICAL Birch R 2010 Surgical Disorders of the Peripheral Nerves, 2nd ed. Edin ­ burgh: Elsevier, Churchill Livingstone.Bogduk N 2012 Clinical and Radiological Anatomy of the Lumbar Spine, 5th ed. Edinburgh: Elsevier, Churchill Livingstone. Borges AF 1984 Relaxed skin tension lines (RSTL) versus other skin lines. Plast Reconstr Surg 73:144–50. Burnand KG, Young AE, Lucas JD, Rowlands B, Scholefield J 2005 The New Aird’s Companion in Surgical Studies, 3rd ed. Edinburgh: Elsevier, Churchill Livingstone. Canale ST, Beaty JH 2012 Campbell’s Operative Orthopaedics, 12th ed. Philadelphia: Elsevier, Mosby. Cormack GC, Lamberty BGH 1994 The Arterial Anatomy of Skin Flaps, 2nd ed. Edinburgh: Elsevier, Churchill Livingstone. Cramer GD, Darby SA 2013 Clinical Anatomy of the Spine, Spinal Cord, and ANS, 3rd ed. MO: Elsevier, Mosby. Dyck PJ, Thomas PK 2005 Peripheral Neuropathy: 2 ­Volume Set with Expert Consult Basic, 4th ed. Philadelphia: Elsevier, WB Saunders. Ellis H, Mahadevan V 2013 Clinical Anatomy: Applied Anatomy for Students and Junior Doctors, 13th ed. Wiley ­Blackwell. Ellis H Feldman S, Harrop ­Griffiths W 2004 Anatomy for Anaesthetists, 8th ed. Oxford: Blackwell Science.Morris SF, Taylor GI 2013 Vascular territories. In: Neligan PC (ed.) Plastic Surgery, vol. I. Principles, 3rd ed. London: Elsevier, Saunders. Rosai J 201 1 Rosai and Ackerman’s Surgical Pathology, 10th ed. London: Elsevier, Mosby. Shah J 2012 Jatin Shah’s Head and Neck Surgery and Oncology: Expert Consult Online and Print, 4th ed. London: Elsevier, Mosby. Zancolli EA, Cozzi EP 1991 Atlas of Surgical Anatomy of the Hand. Edinburgh: Elsevier, Churchill Livingstone. CLINICAL EXAMINATION O’Brien M 2010 Aids to the Examination of the Peripheral Nervous System, 5th ed. London: Elsevier, WB Saunders. Lumley JSP 2008 Surface Anatomy: The Anatomical Basis of Clinical Examination, 4th ed. Edinburgh: Elsevier, Churchill Livingstone.The following references contain information relevant to numerous chapters in this edition. They are therefore cited here rather than at the end of individual chapters. For an extended historical bibliography, all references from the thirty ­eighth edition (which includes all references cited in earlier editions, up to and including the thirty ­eighth edition) are available in the e ­book that accompanies Gray’s Anatomy . TERMINOLOGY Federative Committee on Anatomical Terminology 1998 Terminologia Anatomica: International Anatomical Nomenclature. Stuttgart: Thieme. Dorland WAN 201 1 Dorland’s Illustrated Medical Dictionary, 32nd ed. Philadelphia: Elsevier, WB Saunders. BASIC SCIENCES Abrahams P, Spratt JD, Loukas M, van Schoor A ­N 2013 McMinn and Abrahams’ Clinical Atlas of Human Anatomy: with STUDENT CONSULT Online Access, 7th ed. London: Elsevier, Mosby. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P 2007 Molecu ­ lar Biology of the Cell, 5th ed. New York: Garland Science. Berkovitz BKB, Kirsch C, Moxham BJ, Alusi G, Cheeseman T 2002 Interactive Head and Neck. London: Primal Pictures. Boron WF, Boulpaep E 2012 Medical Physiology: with STUDENT CONSULT Online Access, 2nd ed. Philadelphia: Elsevier, WB Saunders. Crossman AR 2014 Neuroanatomy: An Illustrated Colour Text, 5th ed. Edinburgh: Elsevier, Churchill Livingstone. Fitzgerald MD 201 1 Clinical Neuroanatomy and Neuroscience: with STUDENT CONSULT Online Access, 6th ed. Edinburgh: Elsevier, Saunders. Hall JE 2010 Guyton and Hall Textbook of Medical Physiology: with STUDENT CONSULT Online Access, 12th ed. Philadelphia: Elsevier, Saunders. Kerr JB 2010 Functional Histology, 2nd ed. London: Elsevier, Mosby. Kierszenbaum AL 2014 Histology and Cell Biology: An Introduction to Pathology, 4th ed. St Louis: Elsevier, Mosby. Lowe JS, Anderson PG 2014 Stevens & Lowe’s Human Histology, 4th ed. London: Elsevier, Mosby. Male D, Brostoff J, Roth D, Roitt I 2012 Immunology: with STUDENT CONSULT Online Access, 8th ed. London: Elsevier, Mosby. Moore KL, Persaud TVN, Torchia MG 2015 Before We Are Born: Essen ­ tials of Embryology and Birth Defects, 9th ed. St Louis: Elsevier. Pollard TD, Earnshaw WC 2007 Cell Biology: with STUDENT CONSULT Access, 2nd ed. Philadelphia: Elsevier, WB Saunders. Salmon M 1994 Anatomic Studies: Book 1 Arteries of the Muscles of the Extremities and the Trunk, Book 2 Arterial Anastomotic Pathways of the Extremities. Ed. by Taylor GI, Razaboni RM. St Louis: Quality Medical. Young B, O’Dowd G, Woodford P 2013 Wheater’s Functional Histology: A Text and Colour Atlas, 6th ed. Edinburgh: Elsevier, Churchill Livingstone. IMAGING AND RADIOLOGY/RADIOLOGICAL ANATOMY Butler P, Mitchell AWM, Healy JC 201 1 Applied Radiological Anatomy, 2nd ed. New York: Cambridge University Press. Ellis H, Logan BM, Dixon AK 2007 Human Sectional Anatomy: Pocket Atlas of Body Sections, CT and MRI Images, 3rd ed. CRC Press.

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4SECTION 1 CHAPTER 1 Basic structure and function of cells Epithelial cells rarely operate independently of each other and com- monly form aggregates by adhesion, often assisted by specialized inter - cellular junctions. They may also communicate with each other either by generating and detecting molecular signals that diffuse across inter - cellular spaces, or more rapidly by generating interactions between membrane-bound signalling molecules. Cohesive groups of cells con - stitute tissues, and more complex assemblies of tissues form functional systems or organs. Most cells are between 5 and 50 µm in diameter: e.g. resting lym- phocytes are 6 µm across, red blood cells 7.5 µm and columnar epithe - lial cells 20 µm tall and 10 µm wide (all measurements are approximate). Some cells are much larger than this: e.g. megakaryocytes of the bone marrow and osteoclasts of the remodelling bone are more than 200 µm in diameter. Neurones and skeletal muscle cells have relatively extended shapes, some of the former being over 1 m in length. CELLULAR ORGANIZATION Each cell is contained within its limiting plasma membrane, which encloses the cytoplasm. All cells, except mature red blood cells, also contain a nucleus that is surrounded by a nuclear membrane or enve - lope (see Fig. 1.1; Fig. 1.2). The nucleus includes: the genome of the cell contained within the chromosomes; the nucleolus; and other sub - nuclear structures. The cytoplasm contains cytomembranes and several membrane-bound structures, called organelles, which form separate CELL STRUCTURE GENERAL CHARACTERISTICS OF CELLS The shapes of mammalian cells vary widely depending on their interac - tions with each other, their extracellular environment and internal structures. Their surfaces are often highly folded when absorptive or transport functions take place across their boundaries. Cell size is limited by rates of diffusion, either that of material entering or leaving cells, or that of diffusion within them. Movement of macromolecules can be much accelerated and also directed by processes of active trans - port across the plasma membrane and by transport mechanisms within the cell. According to the location of absorptive or transport functions, apical microvilli (Fig. 1.1) or basolateral infoldings create a large surface area for transport or diffusion. Motility is a characteristic of most cells, in the form of movements of cytoplasm or specific organelles from one part of the cell to another. It also includes: the extension of parts of the cell surface such as pseu - dopodia, lamellipodia, filopodia and microvilli; locomotion of entire cells, as in the amoeboid migration of tissue macrophages; the beating of flagella or cilia to move the cell (e.g. in spermatozoa) or fluids overly - ing it (e.g. in respiratory epithelium); cell division; and muscle contrac - tion. Cell movements are also involved in the uptake of materials from their environment (endocytosis, phagocytosis) and the passage of large molecular complexes out of cells (exocytosis, secretion). Fig . 1 .1 The main structural components and internal organization of a generalized cell . Plasma membraneActin filaments Vesicle Golgi apparatusIntermediate filamentsMitochondrion Smooth endoplasmic reticulum Rough endoplasmic reticulumPeroxisomes CytosolSurface invaginationSurface projections (cilia, microvilli) Cell junctions Desmosome Microtubules Centriole pairNuclear envelope Nucleus RibosomeNucleolus Lysosomes Cell surface foldsNuclear pore

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Cell structure 5 CHaPTER 1 charides and polysaccharides are bound either to proteins (glycopro - teins) or to lipids (glycolipids), and project mainly into the extracellular domain (Fig. 1.3). In the electron microscope, membranes fixed and contrasted by heavy metals such as osmium tetroxide appear in section as two densely stained layers separated by an electron-translucent zone – the classic unit membrane. The total thickness of each layer is about 7.5 nm. The overall thickness of the plasma membrane is typically 15 nm. Freeze- fracture cleavage planes usually pass along the hydrophobic portion of the bilayer, where the hydrophobic tails of phospholipids meet, and split the bilayer into two leaflets. Each cleaved leaflet has a surface and a face. The surface of each leaflet faces either the extracellular surface (ES) or the intracellular or protoplasmic (cytoplasmic) surface (PS). The extracellular face (EF) and protoplasmic face (PF) of each leaflet are artificially produced during membrane splitting. This technique has also demonstrated intramembranous particles embedded in the lipid bilayer; in most cases, these represent large transmembrane protein molecules or complexes of proteins. Intramembranous particles are distributed asymmetrically between the two half-layers, usually adher - ing more to one half of the bilayer than to the other. In plasma mem - branes, the intracellular leaflet carries most particles, seen on its face (the PF). Where they have been identified, clusters of particles usually represent channels for the transmembrane passage of ions or molecules between adjacent cells (gap junctions). Biophysical measurements show the lipid bilayer to be highly fluid, allowing diffusion in the plane of the membrane. Thus proteins are able to move freely in such planes unless anchored from within the cell. Membranes in general, and the plasma membrane in particular, form boundaries selectively limiting diffusion and creating physiologically distinct compartments. Lipid bilayers are impermeable to hydrophilic solutes and ions, and so membranes actively control the passage of ions and small organic molecules such as nutrients, through the activity of membrane transport proteins. However, lipid-soluble substances can pass directly through the membrane so that, for example, steroid hor - mones enter the cytoplasm freely. Their receptor proteins are either cytosolic or nuclear, rather than being located on the cell surface. Plasma membranes are able to generate electrochemical gradients and potential differences by selective ion transport, and actively take up or export small molecules by energy-dependent processes. They also provide surfaces for the attachment of enzymes, sites for the receptors and distinct compartments within the cytoplasm. Cytomembranes include the rough and smooth endoplasmic reticulum and Golgi appa- ratus, as well as vesicles derived from them. Organelles include lyso - somes, peroxisomes and mitochondria. The nucleus and mitochondria are enclosed by a double-membrane system; lysosomes and peroxi - somes have a single bounding membrane. There are also non-membranous structures, called inclusions, which lie free in the cytosolic compartment. They include lipid droplets, glycogen aggregates and pig - ments (e.g. lipofuscin). In addition, ribosomes and several filamentous protein networks, known collectively as the cytoskeleton, are found in the cytosol. The cytoskeleton determines general cell shape and sup - ports specialized extensions of the cell surface (microvilli, cilia, flag - ella). It is involved in the assembly of specific structures (e.g. centrioles) and controls cargo transport in the cytoplasm. The cytosol contains many soluble proteins, ions and metabolites. Plasma membrane Cells are enclosed by a distinct plasma membrane, which shares fea - tures with the cytomembrane system that compartmentalizes the cyto - plasm and surrounds the nucleus. All membranes are composed of lipids (mainly phospholipids, cholesterol and glycolipids) and pro - teins, in approximately equal ratios. Plasma membrane lipids form a lipid bilayer, a layer two molecules thick. The hydrophobic ends of each lipid molecule face the interior of the membrane and the hydrophilic ends face outwards. Most proteins are embedded within, or float in, the lipid bilayer as a fluid mosaic. Some proteins, because of extensive hydrophobic regions of their polypeptide chains, span the entire width of the membrane (transmembrane proteins), whereas others are only superficially attached to the bilayer by lipid groups. Both are integral (intrinsic) membrane proteins, as distinct from peripheral (extrinsic) membrane proteins, which are membrane-bound only through their association with other proteins. Carbohydrates in the form of oligosac- Fig . 1 .2 The structural organization and some principal organelles of a typical cell . This example is a ciliated columnar epithelial cell from human nasal mucosa . The central cell, which occupies most of the field of view, is closely apposed to its neighbours along their lateral plasma membranes . Within the apical junctional complex, these membranes form a tightly sealed zone (tight junction) that isolates underlying tissues from, in this instance, the nasal cavity . Abbreviations: AJC, apical junctional complex; APM, apical plasma membrane; C, cilia; Cy, cytoplasm; EN, euchromatic nucleus; LPM, lateral plasma membrane; M, mitochondria; MV, microvilli; N, nucleolus . (Courtesy of Dr Bart Wagner, Histopathology Department, Sheffield Teaching Hospitals, UK .) C MV M Cy LPM N ENMAPMAJCV M C M Cy LPM N ENMAPMAJC Fig . 1 .3 The molecular organization of the plasma membrane, according to the fluid mosaic model of membrane structure . Intrinsic or integral membrane proteins include diffusion or transport channel complexes, receptor proteins and adhesion molecules . These may span the thickness of the membrane (transmembrane proteins) and can have both extracellular and cytoplasmic domains . Transmembrane proteins have hydrophobic zones, which cross the phospholipid bilayer and allow the protein to ‘float’ in the plane of the membrane . Some proteins are restricted in their freedom of movement where their cytoplasmic domains are tethered to the cytoskeleton . Receptor protein Lipid bilayer appearancein electronmicroscopeInternal (intracellular) surfaceCarbohydrateresidues TransmembraneproteinIntrinsic membrane protein Transport or diffusion channelExtrinsic proteinTransmembrane pore complex of proteins External (extracellular) surface Polar end ofphospholipidNon-polar tailof phospholipid Cytoskeletalelement

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Basic structure and function of cells 5.e1 CHaPTER 1 Combinations of biochemical, biophysical and biological tech - niques have revealed that lipids are not homogenously distributed in membranes, but that some are organized into microdomains in the bilayer, called ‘detergent-resistant membranes’ or lipid ‘rafts’, rich in sphingomyelin and cholesterol. The ability of select subsets of proteins to partition into different lipid microdomains has profound effects on their function, e.g. in T-cell receptor and cell–cell signalling. The highly organized environment of the domains provides a signalling, trafficking and membrane fusion environment.

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BaSIC STR uCTuRE aNd fu NCTION Of CEllS 6SECTION 1 abundant proteins; SER is abundant in steroid-producing cells and muscle cells. A variant of the endoplasmic reticulum in muscle cells is the sarcoplasmic reticulum, involved in calcium storage and release for muscle contraction. For further reading on the endoplasmic reticulum, see Bravo et al (2013). Smooth endoplasmic reticulum The smooth endoplasmic reticulum (see Fig. 1.4) is associated with carbohydrate metabolism and many other metabolic processes, includ - ing detoxification and synthesis of lipids, cholesterol and steroids. The membranes of the smooth endoplasmic reticulum serve as surfaces for the attachment of many enzyme systems, e.g. the enzyme cytochrome P450, which is involved in important detoxification mechanisms and is thus accessible to its substrates, which are generally lipophilic. The membranes also cooperate with the rough endoplasmic reticulum and the Golgi apparatus to synthesize new membranes; the protein, carbohydrate and lipid components are added in different structural compartments. The smooth endoplasmic reticulum in hepatocytes con - tains the enzyme glucose-6-phosphatase, which converts glucose-6- phosphate to glucose, a step in gluconeogenesis. Rough endoplasmic reticulum The rough endoplasmic reticulum is a site of protein synthesis; its cytosolic surface is studded with ribosomes ( Fig. 1.5E). Ribosomes only bind to the endoplasmic reticulum when proteins targeted for secretion begin to be synthesized. Most proteins pass through its membranes and accumulate within its cisternae, although some integral membrane pro - teins, e.g. plasma membrane receptors, are inserted into the rough endoplasmic reticulum membrane, where they remain. After passage from the rough endoplasmic reticulum, proteins remain in membrane- bound cytoplasmic organelles such as lysosomes, become incorporated into new plasma membrane, or are secreted by the cell. Some carbohy - drates are also synthesized by enzymes within the cavities of the rough endoplasmic reticulum and may be attached to newly formed protein (glycosylation). Vesicles are budded off from the rough endoplasmic reticulum for transport to the Golgi as part of the protein-targeting mechanism of the cell. Ribosomes, polyribosomes and protein synthesis Ribosomes are macromolecular machines that catalyse the synthesis of proteins from amino acids; synthesis and assembly into subunits takes place in the nucleolus and includes the association of ribosomal RNA (rRNA) with ribosomal proteins translocated from their site of synthesis in the cytoplasm. The individual subunits are then transported into the cytoplasm, where they remain separate from each other when not actively synthesizing proteins. Ribosomes are granules approximately 25 nm in diameter, composed of rRNA molecules and proteins assem - bled into two unequal subunits. The subunits can be separated by their sedimentation coefficients (S) in an ultracentrifuge into larger 60S and smaller 40S components. These are associated with 73 different pro - teins (40 in the large subunit and 33 in the small), which have structural and enzymatic functions. Three small, highly convoluted rRNA strands (28S, 5.8S and 5S) make up the large subunit, and one strand (18S) is in the small subunit. A typical cell contains millions of ribosomes. They may form groups (polyribosomes or polysomes) attached to messenger RNA (mRNA), which they translate during protein synthesis for use outside the system of membrane compartments, e.g. enzymes of the cytosol and cytoskel - etal proteins. Some of the cytosolic products include proteins that can be inserted directly into (or through) membranes of selected organelles, such as mitochondria and peroxisomes. Ribosomes may be attached to the membranes of the rough endoplasmic reticulum (see Fig. 1.5E). In a mature polyribosome, all the attachment sites of the mRNA are occupied as ribosomes move along it, synthesizing protein according to its nucleotide sequence. Consequently, the number and spacing of ribosomes in a polyribosome indicate the length of the mRNA mole - cule and hence the size of the protein being made. The two subunits have separate roles in protein synthesis. The 40S subunit is the site of attachment and translation of mRNA. The 60S subunit is responsible for the release of the new protein and, where appropriate, attachment to the endoplasmic reticulum via an intermediate docking protein that directs the newly synthesized protein through the membrane into the cisternal space. Golgi apparatus (Golgi complex) The Golgi apparatus is a distinct cytomembrane system located near the nucleus and the centrosome. It is particularly prominent in secretory cells and can be visualized when stained with silver or other metallic of external signals, including hormones and other ligands, and sites for the recognition and attachment of other cells. Internally, plasma mem - branes can act as points of attachment for intracellular structures, in particular those concerned with cell motility and other cytoskeletal functions. Cell membranes are synthesized by the rough endoplasmic reticulum in conjunction with the Golgi apparatus. Cell coat (glycocalyx) The external surface of a plasma membrane differs structurally from internal membranes in that it possesses an external, fuzzy, carbohydrate- rich coat, the glycocalyx. The cell coat forms an integral part of the plasma membrane, projecting as a diffusely filamentous layer 2–20 nm or more from the lipoprotein surface. The cell coat is composed of the carbohydrate portions of glycoproteins and glycolipids embedded in the plasma membrane (see Fig. 1.3). The precise composition of the glycocalyx varies with cell type; many tissue- and cell type-specific antigens are located in the coat, including the major histocompatibility complex of the immune system and, in the case of erythrocytes, blood group antigens. Therefore, the glycocalyx plays a significant role in organ transplant compatibility. The glycocalyx found on apical microvilli of enterocytes, the cells forming the lining epithelium of the intestine, consists of enzymes involved in the diges - tive process. Intestinal microvilli are cylindrical projections (1–2 µm long and about 0.1 µm in diameter) forming a closely packed layer called the brush border that increases the absorptive function of enterocytes. Cytoplasm Compartments and functional organization The cytoplasm consists of the cytosol, a gel-like material enclosed by the cell or plasma membrane. The cytosol is made up of colloidal pro - teins such as enzymes, carbohydrates and small protein molecules, together with ribosomes and ribonucleic acids. The cytoplasm contains two cytomembrane systems, the endoplasmic reticulum and Golgi apparatus, as well as membrane-bound organelles (lysosomes, peroxi - somes and mitochondria), membrane-free inclusions (lipid droplets, glycogen and pigments) and the cytoskeleton. The nuclear contents, the nucleoplasm, are separated from the cytoplasm by the nuclear envelope. Endoplasmic reticulum The endoplasmic reticulum is a system of interconnecting membrane-lined channels within the cytoplasm ( Fig. 1.4). These channels take various forms, including cisternae (flattened sacs), tubules and vesicles. The membranes divide the cytoplasm into two major compartments. The intramembranous compartment, or cisternal space, is where secre - tory products are stored or transported to the Golgi complex and cell exterior. The cisternal space is continuous with the perinuclear space. Structurally, the channel system can be divided into rough or granu - lar endoplasmic reticulum (RER), which has ribosomes attached to its outer, cytosolic surface, and smooth or agranular endoplasmic reticu- lum (SER), which lacks ribosomes. The functions of the endoplasmic reticulum vary greatly and include: the synthesis, folding and transport of proteins; synthesis and transport of phospholipids and steroids; and storage of calcium within the cisternal space and regulated release into the cytoplasm. In general, RER is well developed in cells that produce Fig . 1 .4 Smooth endoplasmic reticulum with associated vesicles . The dense particles are glycogen granules . (Courtesy of Rose Watson, Cancer Research UK .)

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Basic structure and function of cells 6.e1 CHaPTER 1 The glycocalyx plays a significant role in maintenance of the integrity of tissues and in a wide range of dynamic cellular processes, e.g. serving as a vascular permeability barrier and transducing fluid shear stress to the endothelial cell cytoskeleton (Weinbaum et al 2007). Disruption of the glycocalyx on the endothelial surface of large blood vessels precedes inflammation, a conditioning factor of atheromatosis (e.g. deposits of cholesterol in the vascular wall leading to partial or complete obstruc - tion of the vascular lumen). Protein synthesis on ribosomes may be suppressed by a class of RNA molecules known as small interfering RNA (siRNA) or silencing RNA. These molecules are typically 20–25 nucleotides in length and bind (as a complex with proteins) to specific mRNA molecules via their comple - mentary sequence. This triggers the enzymatic destruction of the mRNA or prevents the movement of ribosomes along it. Synthesis of the encoded protein is thus prevented. Their normal function may have antiviral or other protective effects; there is also potential for developing artificial siRNAs as a therapeutic tool for silencing disease-related genes.

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Cell structure 7 CHaPTER 1 Fig . 1 .5 The Golgi apparatus and functionally related organelles . A, Golgi apparatus (G) adjacent to the nucleus (N) (V, vesicle) . B, A large residual body (tertiary lysosome) in a cardiac muscle cell (M, mitochondrion) . C, The functional relationships between the Golgi apparatus and associated cellular structures . D, A three-dimensional reconstruction of the Golgi apparatus in a pancreatic β cell showing stacks of Golgi cisternae from the cis-face (pink) and cis-medial cisternae (red, green) to the trans-Golgi network (blue, yellow, orange–red); immature proinsulin granules (condensing vesicles) are shown in pale blue and mature (crystalline) insulin granules in dark blue . The flat colour areas represent cut faces of cisternae and vesicles . E, Rough endoplasmic reticulum (R), associated with the Golgi apparatus (G) . (D, Courtesy of Dr Brad Marsh, Institute for Molecular Bioscience, University of Queensland, Brisbane . A,B,E From human tissue, courtesy of Dr Bart Wagner, Histopathology Department, Sheffield Teaching Hospitals, UK .) M Phagocytic pathway Secretory pathway Receptor-mediated endocytosis Membrane recycling Early endosome Late endosome Secondary lysosome Residual body cis-Golgi network Rough endoplasmic reticulumGolgi cisternaeVesicle shuttling between cisternaeLysosomal fusionClathrin-coated pit trans-Golgi networkA B C D EG VN G G RG G

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BaSIC STR uCTuRE aNd fu NCTION Of CEllS 8SECTION 1 Endocytic (internalization) pathway The endocytic pathway begins at the plasma membrane and ends in lysosomes involved in the degradation of the endocytic cargo through the enzymatic activity of lysosomal hydrolases. Endocytic cargo is internalized from the plasma membrane to early endosomes and then to late endosomes. Late endosomes transport their cargo to lyso - somes, where the cargo material is degraded following fusion and mixing of contents of endosomes and lysosomes. Early endosomes derive from endocytic vesicles (clathrin-coated vesicles and caveolae). Once internalized, endocytic vesicles shed their coat of adaptin and clathrin, and fuse to form an early endosome, where the receptor molecules release their bound ligands. Membrane and receptors from the early endosomes can be recycled to the cell surface as exocytic vesicles. Clathrin-dependent endocytosis occurs at specialized patches of plasma membrane called coated pits; this mechanism is also used to internalize ligands bound to surface receptor molecules and is also termed receptor-mediated endocytosis. Caveolae (little caves) are struc - turally distinct pinocytotic vesicles most widely used by endothelial and smooth muscle cells, when they are involved in transcytosis, signal transduction and possibly other functions. In addition to late endo - somes, lysosomes can also fuse with phagosomes, autophagosomes and plasma membrane patches for membrane repair. Lysosomal hydro - lases process or degrade exogenous materials (phagocytosis or hetero - phagy) as well as endogenous material (autophagy). Phagocytosis consists of the cellular uptake of invading pathogens, apoptotic cells and other foreign material by specialized cells. Lysosomes are numerous in actively phagocytic cells, e.g. macrophages and neutrophil granulo- cytes, in which lysosomes are responsible for destroying phagocytosed particles, e.g. bacteria. In these cells, the phagosome, a vesicle poten - tially containing a pathogenic microorganism, may fuse with several lysosomes. Autophagy involves the degradation and recycling within an autophagosome of cytoplasmic components that are no longer needed, including organelles. The assembly of the autophagosome involves several proteins, including autophagy-related (Atg) proteins, as well as Hsc70 chaperone, that translocate the substrate into the lysosome (Boya et al 2013). Autophagosomes sequester cytoplasmic components and then fuse with lysosomes without the participation of a late endosome. The 26S proteasome (see below) is also involved in cellular degradation but autophagy refers specifically to a lysosomal degradation–recycling pathway. Autophagosomes are seen in response to starvation and cell growth. Late endosomes receive lysosomal enzymes from primary lysosomes derived from the Golgi apparatus after late endosome–lysosome mem - brane tethering and fusion followed by diffusion of lysosomal contents into the endosomal lumen. The pH inside the fused hybrid organelle, now a secondary lysosome, is low (about 5.0) and this activates lyso - somal acid hydrolases to degrade the endosomal contents. The products of hydrolysis either are passed through the membrane into the cytosol, or may be retained in the secondary lysosome. Secondary lysosomes may grow considerably in size by vesicle fusion to form multivesicular bodies, and the enzyme concentration may increase greatly to form large lysosomes ( Fig. 1.5B). Lysosomes Lysosomes are membrane-bound organelles 80–800 nm in diameter, often with complex inclusions of material undergoing hydrolysis (sec - ondary lysosomes). Two classes of proteins participate in lysosomal function: soluble acid hydrolases and integral lysosomal membrane proteins. Each of the 50 known acid hydrolases (including proteases, lipases, carbohydrases, esterases and nucleases) degrades a specific sub - strate. There are about 25 lysosomal membrane proteins participating in the acidification of the lysosomal lumen, protein import from the cytosol, membrane fusion and transport of degradation products to the cytoplasm. Material that has been hydrolysed within secondary lyso - somes may be completely degraded to soluble products, e.g. amino acids, which are recycled through metabolic pathways. However, degra - dation is usually incomplete and some debris remains. A debris-laden vesicle is called a residual body or tertiary lysosome (see Fig. 1.5B), and may be passed to the cell surface, where it is ejected by exocytosis; alternatively, it may persist inside the cell as an inert residual body. Considerable numbers of residual bodies can accumulate in long-lived cells, often fusing to form larger dense vacuoles with complex lamellar inclusions. As their contents are often darkly pigmented, this may change the colour of the tissue; e.g. in neurones, the end-product of lysosomal digestion, lipofuscin (neuromelanin or senility pigment), gives ageing brains a brownish-yellow colouration. Lysosomal enzymes salts. Traffic between the endoplasmic reticulum and the Golgi appara - tus is bidirectional and takes place via carrier vesicles derived from the donor site that bud, tether and fuse with the target site. Golgins are long coiled-coil proteins attached to the cytoplasmic surface of cisternal membranes, forming a fibrillar matrix surrounding the Golgi apparatus to stabilize it; they have a role in vesicle trafficking (for further reading on golgins, see Munro 201 1). The Golgi apparatus has several functions: it links anterograde and retrograde protein and lipid flow in the secretory pathway; it is the site where protein and lipid glycosylation occurs; and it provides membrane platforms to which signalling and sorting proteins bind. Ultrastructurally, the Golgi apparatus (Fig. 1.5A) displays a contin- uous ribbon-like structure consisting of a stack of several flattened membranous cisternae, together with clusters of vesicles surrounding its surfaces. Cisternae differ in enzymatic content and activity. Small transport vesicles from the rough endoplasmic reticulum are received at one face of the Golgi stack, the convex cis-face (entry or forming surface). Here, they deliver their contents to the first cisterna in the series by membrane fusion. From the edges of this cisterna, the protein is transported to the next cisterna by vesicular budding and then fusion, and this process is repeated across medial cisternae until the final cisterna at the concave trans-face (exit or condensing surface) is reached. Here, larger vesicles are formed for delivery to other parts of the cell. The cis-Golgi and trans-Golgi membranous networks form an inte - gral part of the Golgi apparatus. The cis-Golgi network is a region of complex membranous channels interposed between the rough endo - plasmic reticulum and the Golgi cis-face, which receives and transmits vesicles in both directions. Its function is to select appropriate proteins synthesized on the rough endoplasmic reticulum for delivery by vesicles to the Golgi stack, while inappropriate proteins are shuttled back to the rough endoplasmic reticulum. The trans-Golgi network, at the other side of the Golgi stack, is also a region of interconnected membrane channels engaged in protein sorting. Here, modified proteins processed in the Golgi cisternae are packaged selectively into vesicles and dispatched to different parts of the cell. The packaging depends on the detection, by the trans-Golgi network, of particular amino-acid signal sequences, leading to their enclosure in membranes of appropriate composition that will further modify their contents, e.g. by extracting water to concentrate them (vesicles entering the exocytosis pathway) or by pumping in protons to acidify their contents (lysosomes destined for the intracellular sorting pathway). Within the Golgi stack proper, proteins undergo a series of sequen - tial chemical modifications by Golgi resident enzymes synthesized in the rough endoplasmic reticulum. These include: glycosylation (changes in glycosyl groups, e.g. removal of mannose, addition of N-acetylglucosamine and sialic acid); sulphation (addition of sulphate groups to glycosaminoglycans); and phosphorylation (addition of phosphate groups). Some modifications serve as signals to direct pro - teins and lipids to their final destination within cells, including lyso-somes and plasma membrane. Lipids formed in the endoplasmic reticulum are also routed for incorporation into vesicles. Exocytic (secretory) pathway Secreted proteins, lipids, glycoproteins, small molecules such as amines and other cellular products destined for export from the cell are trans - ported to the plasma membrane in small vesicles released from the trans-face of the Golgi apparatus. This pathway either is constitutive, in which transport and secretion occur more or less continuously, as with immunoglobulins produced by plasma cells, or it is regulated by exter- nal signals, as in the control of salivary secretion by autonomic neural stimulation. In regulated secretion, the secretory product is stored tem - porarily in membrane-bound secretory granules or vesicles. Exocytosis is achieved by fusion of the secretory vesicular membrane with the plasma membrane and release of the vesicle contents into the extracel- lular domain. In polarized cells, e.g. most epithelia, exocytosis occurs at the apical plasma membrane. Glandular epithelial cells secrete into a duct lumen, as in the pancreas, or on to a free surface, such as the lining of the stomach. In hepatocytes, bile is secreted across a very small area of plasma membrane forming the wall of the bile canaliculus. This region is defined as the apical plasma membrane and is the site of exocrine secretion, whereas secretion of hepatocyte plasma proteins into the blood stream is targeted to the basolateral surfaces facing the sinusoids. Packaging of different secretory products into appropriate vesicles takes place in the trans-Golgi network. Delivery of secretory vesicles to their correct plasma membrane domains is achieved by sorting sequences in the cytoplasmic tails of vesicular membrane proteins.

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Basic structure and function of cells 8.e1 CHaPTER 1 Carrier vesicles in transit from the endoplasmic reticulum to the Golgi apparatus (anterograde transport) are coated by coat protein complex II (COPII), whereas COPI-containing vesicles function in the retrograde transport route from the Golgi apparatus (reviewed in Spang (2013)). The membranes contain specific signal proteins that may allocate them to microtubule-based transport pathways and allow them to dock with appropriate targets elsewhere in the cell, e.g. the plasma mem - brane in the case of secretory vesicles. Vesicle formation and budding at the trans-Golgi network involves the addition of clathrin on their external surface, to form coated pits. Specialized cells of the immune system, called antigen-presenting cells, degrade protein molecules, called antigens, transported by the endocytic pathway for lysosomal breakdown, and expose their frag - ments to the cell exterior to elicit an immune response mediated ini - tially by helper T cells.

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Cell structure 9 CHaPTER 1 Mitochondria In the electron microscope, mitochondria usually appear as round or elliptical bodies 0.5–2.0 µm long ( Fig. 1.6), consisting of an outer mitochondrial membrane; an inner mitochrondrial membrane, sepa- rated from the outer membrane by an intermembrane space; cristae, infoldings of the inner membrane that harbour ATP synthase to gener - ate ATP; and the mitochondrial matrix, a space enclosed by the inner membrane and numerous cristae. The permeability of the two mito - chondrial membranes differs considerably: the outer membrane is freely permeable to many substances because of the presence of large non-specific channels formed by proteins (porins), whereas the inner membrane is permeable to only a narrow range of molecules. The pres - ence of cardiolipin, a phospholipid, in the inner membrane may con - tribute to this relative impermeability. Mitochondria are the principal source of chemical energy in most cells. Mitochondria are the site of the citric acid (Krebs’) cycle and the electron transport (cytochrome) pathway by which complex organic molecules are finally oxidized to carbon dioxide and water. This process provides the energy to drive the production of ATP from adenosine diphosphate (ADP) and inorganic phosphate (oxidative phosphoryla - tion). The various enzymes of the citric acid cycle are located in the mitochondrial matrix, whereas those of the cytochrome system and oxidative phosphorylation are localized chiefly in the inner mitochon - drial membrane. The intermembrane space houses cytochrome c, a molecule involved in activation of apoptosis. The number of mitochondria in a particular cell reflects its general energy requirements; e.g. in hepatocytes there may be as many as 2000, whereas in resting lymphocytes there are usually very few. Mature may also be secreted – often as part of a process to alter the extracellular matrix, as in osteoclast-mediated erosion during bone resorption. For further reading on lysosome biogenesis, see Saftig and Klumperman (2009). lysosomal dysfunction Lysosomal storage diseases (LSDs) are a consequence of lysosomal dysfunction. Approximately 60 different types of LSD have been identi - fied on the basis of the type of material accumulated in cells (such as mucopolysaccharides, sphingolipids, glycoproteins, glycogen and lipo - fuscins). LSDs are characterized by severe neurodegeneration, mental decline, and cognitive and behavioural abnormalities. Autophagy impairment caused by defective lysosome–autophagosome coupling triggers a pathogenic cascade by the accumulation of substrates that contribute to neurodegenerative disorders including Parkinson’s dis - ease, Alzheimer’s disease, Huntington’s disease and several tau-opathies. Many lysosomal storage diseases are known, e.g. Tay–Sachs disease (GM2 gangliosidosis), in which a faulty β-hexosaminidase A leads to the accumulation of the glycosphingolipid GM2 ganglioside in neu - rones, causing death during childhood. In Danon disease, a vacuolar skeletal myopathy and cardiomyopathy with neurodegeneration in hemizygous males, lysosomes fail to fuse with autophagosomes because of a mutation of the lysosomal membrane protein LAMP-2 (lysosomal associated membrane protein-2). 26S proteasome A protein can be degraded by different mechanisms, depending on the cell type and different pathological conditions. Furthermore, the same substrate can engage different proteolytic pathways (Park and Cuervo 2013). Three major protein degradation mechanisms operate in eukaryotic cells to dispose of non-functional cellular proteins: the autophagosome–lysosomal pathway (see above); the apoptotic procaspase–caspase pathway (see below); and the ubiquitinated protein–26S proteasome pathway. The 26S proteasome is a multicata - lytic protease found in the cytosol and the nucleus that degrades intra - cellular proteins conjugated to a polyubiquitin chain by an enzymatic cascade. The 26S proteasome consists of several subunits arranged into two 19S polar caps, where protein recognition and adenosine 5 ′- triphosphate (ATP)-dependent target processing occur, flanking a 20S central barrel-shaped structure with an inner proteolytic chamber (Tomko and Hochstrasser 2013). The 26S proteasome participates in the removal of misfolded or abnormally assembled proteins, the deg - radation of cyclins involved in the control of the cell cycle, the process - ing and degradation of transcription regulators, cellular-mediated immune responses, and cell cycle arrest and apoptosis. Peroxisomes Peroxisomes are small (0.2–1 µm in diameter) membrane-bound organelles present in most mammalian cells. They contain more than 50 enzymes responsible for multiple catabolic and synthetic biochemi - cal pathways, in particular the β-oxidation of very-long-chain fatty acids (>C22) and the metabolism of hydrogen peroxide (hence the name peroxisome). Peroxisomes derive from the endoplasmic reticu - lum through the transfer of proteins from the endoplasmic reticulum to peroxisomes by vesicles that bud from specialized sites of the endo - plasmic reticulum and by a lipid non-vesicular pathway. All matrix proteins and some peroxisomal membrane proteins are synthesized by cytosolic ribosomes and contain a peroxisome targeting signal that enables them to be imported by proteins called peroxins (Braverman et al 2013, Theodoulou et al 2013). Mature peroxisomes divide by small daughter peroxisomes pinching off from a large parental peroxisome. Peroxisomes often contain crystalline inclusions composed mainly of high concentrations of the enzyme urate oxidase. Oxidases use molecular oxygen to oxidize specific organic substrates (such as L-amino acids, D-amino acids, urate, xanthine and very-long-chain fatty acids) and produce hydrogen peroxide that is detoxified (degraded) by per - oxisomal catalase. Peroxisomes are particularly numerous in hepato - cytes. Peroxisomes are important in the oxidative detoxification of various substances taken into or produced within cells, including ethanol. Peroxin mutation is a characteristic feature of Zellweger syn - drome (craniofacial dysmorphism and malformations of brain, liver, eye and kidney; cerebrohepatorenal syndrome). Neonatal leukodystro - phy is an X-linked peroxisomal disease affecting mostly males, caused by deficiency in β-oxidation of very-long-chain fatty acids. The build-up of very-long-chain fatty acids in the nervous system and suprarenal glands determines progressive deterioration of brain function and suprarenal insufficiency (Addison’s disease). For further reading, see Braverman et al (2013). Fig . 1 .6 A, Mitochondria in human cardiac muscle . The folded cristae (arrows) project into the matrix from the inner mitochondrial membrane . B, The location of the elementary particles that couple oxidation and phosphorylation reactions . (A, Courtesy of Dr Bart Wagner, Histopathology Department, Sheffield Teaching Hospitals, UK .) A B Elementary particlesCristae (folds)Inner membraneOuter membrane

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Basic structure and function of cells 9.e1 CHaPTER 1 The transcription factor EB (TFEB) is responsible for regulating lyso - somal biogenesis and function, lysosome-to-nucleus signalling and lipid catabolism (for further reading, see Settembre et al (2013)). If any of the actions of lysosomal hydrolases, of the lysosome acidification mechanism or of lysosomal membrane proteins fails, the degradation and recycling of extracellular substrates delivered to lysosomes by the late endosome and the degradation and recycling of intracellular sub - strates by autophagy lead to progressive lysosomal dysfunction in several tissues and organs. Experimentally, TFEB activation can reduce the accumulation of the pathogenic protein in a cellular model of Huntington’s disease (a neurodegenerative genetic disorder that affects muscle coordination) and improves the Parkinson’s disease phenotype in a murine model. Cristae are abundant in mitochondria seen in cardiac muscle cells and in steroid-producing cells (in the suprarenal cortex, corpus luteum and Leydig cells). The protein steroidogenic acute regulatory protein (StAR) regulates the synthesis of steroids by transporting cholesterol across the outer mitochondrial membrane. A mutation in the gene encoding StAR causes defective suprarenal and gonadal steroidogenesis.

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BaSIC STR uCTuRE aNd fu NCTION Of CEllS 10 SECTION 1 ent and its electronic charge, and the potential difference across the membrane. These factors combine to produce an electrochemical gradi - ent, which governs ion flux. Channel proteins are utilized most effec - tively by the excitable plasma membranes of nerve cells, where the resting membrane potential can change transiently from about −80 mV (negative inside the cell) to +40 mV (positive inside the cell) when stimulated by a neurotransmitter (as a result of the opening and sub - sequent closure of channels selectively permeable to sodium and potassium). Carrier proteins bind their specific solutes, such as amino acids, and transport them across the membrane through a series of conforma - tional changes. This latter process is slower than ion transport through membrane channels. Transport by carrier proteins can occur either pas - sively by simple diffusion, or actively against the electrochemical gradi - ent of the solute. Active transport must therefore be coupled to a source of energy, such as ATP generation, or energy released by the coordinate movement of an ion down its electrochemical gradient. Linked trans - port can be in the same direction as the solute, in which case the carrier protein is described as a symporter, or in the opposite direction, when the carrier acts as an antiporter. Translocation of proteins across intracellular membranes Proteins are generally synthesized on ribosomes in the cytosol or on the rough endoplasmic reticulum. A few are made on mitochondrial ribosomes. Once synthesized, many proteins remain in the cytosol, where they carry out their functions. Others, such as integral membrane proteins or proteins for secretion, are translocated across intracellular membranes for post-translational modification and targeting to their destinations. This is achieved by the signal sequence, an addressing system contained within the protein sequence of amino acids, which is recognized by receptors or translocators in the appropriate membrane. Proteins are thus sorted by their signal sequence (or set of sequences that become spatially grouped as a signal patch when the protein folds into its tertiary configuration), so that they are recognized by and enter the correct intracellular membrane compartment. Cell signalling Cellular systems in the body communicate with each other to coordi - nate and integrate their functions. This occurs through a variety of processes known collectively as cell signalling, in which a signalling molecule produced by one cell is detected by another, almost always by means of a specific receptor protein molecule. The recipient cell trans - duces the signal, which it most often detects at the plasma membrane, into intracellular chemical messages that change cell behaviour. The signal may act over a long distance, e.g. endocrine signalling through the release of hormones into the blood stream, or neuronal synaptic signalling via electrical impulse transmission along axons and subsequent release of chemical transmitters of the signal at syn - apses or neuromuscular junctions. A specialized variation of endocrine signalling (neurocrine or neuroendocrine signalling) occurs when neu - rones or paraneurones (e.g. chromaffin cells of the suprarenal medulla) secrete a hormone into interstitial fluid and the blood stream. Alternatively, signalling may occur at short range through a paracrine mechanism, in which cells of one type release molecules into the inter - stitial fluid of the local environment, to be detected by nearby cells of a different type that express the specific receptor protein. Neurocrine cell signalling uses chemical messengers found also in the central nervous system, which may act in a paracrine manner via interstitial fluid or reach more distant target tissues via the blood stream. Cells may generate and respond to the same signal. This is autocrine signal - ling, a phenomenon that reinforces the coordinated activities of a group of like cells, which respond together to a high concentration of a local signalling molecule. The most extreme form of short-distance signalling is contact-dependent (juxtacrine) signalling, where one cell responds to transmembrane proteins of an adjacent cell that bind to surface recep - tors in the responding cell membrane. Contact-dependent signalling also includes cellular responses to integrins on the cell surface binding to elements of the extracellular matrix. Juxtacrine signalling is impor - tant during development and in immune responses. These different types of intercellular signalling mechanism are illustrated in Figure 1.7. For further reading on cell signalling pathways, see Kierszenbaum and Tres (2012). Signalling molecules and their receptors The majority of signalling molecules (ligands) are hydrophilic and so cannot cross the plasma membrane of a recipient cell to effect changes erythrocytes lack mitochondria altogether. Cells with few mitochondria generally rely largely on glycolysis for their energy supplies. These include some very active cells, e.g. fast twitch skeletal muscle fibres, which are able to work rapidly but for only a limited duration. Mito - chondria appear in the light microscope as long, thin structures in the cytoplasm of most cells, particularly those with a high metabolic rate, e.g. secretory cells in exocrine glands. In living cells, mitochondria constantly change shape and intracellular position; they multiply by growth and fission, and may undergo fusion. The mitochondrial matrix is an aqueous environment. It contains a variety of enzymes, and strands of mitochondrial DNA with the capacity for transcription and translation of a unique set of mitochondrial genes (mitochondrial mRNAs and transfer RNAs, mitochondrial ribosomes with rRNAs). The DNA forms a closed loop, about 5 µm across; several identical copies are present in each mitochondrion. The ratio between its bases differs from that of nuclear DNA, and the RNA sequences also differ in the precise genetic code used in protein synthesis. At least 13 respiratory chain enzymes of the matrix and inner membrane are encoded by the small number of genes along the mitochondrial DNA. The great majority of mitochondrial proteins are encoded by nuclear genes and made in the cytosol, then inserted through special channels in the mitochondrial membranes to reach their destinations. Their membrane lipids are synthesized in the endoplasmic reticulum. It has been shown that mitochondria are of maternal origin because the mitochondria of spermatozoa are not generally incorporated into the ovum at fertilization. Thus mitochondria (and mitochondrial genetic variations and mutations) are passed only through the female line. Mitochondria are distributed within a cell according to regional energy requirements, e.g. near the bases of cilia in ciliated epithelia, in the basal domain of the cells of proximal convoluted tubules in the renal cortex (where considerable active transport occurs) and around the proximal segment, called middle piece, of the flagellum in sperma - tozoa. They may be involved with tissue-specific metabolic reactions, e.g. various urea-forming enzymes are found in liver cell mitochondria. Moreover, a number of genetic diseases of mitochondria affect particu - lar tissues exclusively, e.g. mitochondrial myopathies (skeletal muscle) and mitochondrial neuropathies (nervous tissue). For further informa - tion on mitochondrial genetics and disorders, see Chinnery and Hudson (2013). Cytosolic inclusions The aqueous cytosol surrounds the membranous organelles described above. It also contains various non-membranous inclusions, including free ribosomes, components of the cytoskeleton, and other inclusions, such as storage granules (e.g. glycogen), pigments (such as lipofuscin granules, remnants of the lipid oxidative mechanism seen in the supra - renal cortex) and lipid droplets. lipid droplets Lipid droplets are spherical bodies of various sizes found within many cells, but are especially prominent in the adipocytes (fat cells) of adipose connective tissue. They do not belong to the Golgi-related vacu - olar system of the cell. They are not membrane-bound, but are droplets of lipid suspended in the cytosol and surrounded by perilipin proteins, which regulate lipid storage and lipolysis. See Smith and Ordovás (2012) for further reading on obesity and perilipins. In cells specialized for lipid storage, the vacuoles reach 80 µm or more in diameter. They function as stores of chemical energy, thermal insulators and mechani - cal shock absorbers in adipocytes. In many cells, they may represent end-products of other metabolic pathways, e.g. in steroid-synthesizing cells, where they are a prominent feature of the cytoplasm. They may also be secreted, as in the alveolar epithelium of the lactating breast. Transport across cell membranes Lipid bilayers are increasingly impermeable to molecules as they increase in size or hydrophobicity. Transport mechanisms are therefore required to carry essential polar molecules, including ions, nutrients, nucleotides and metabolites of various kinds, across the plasma mem - brane and into or out of membrane-bound intracellular compartments. Transport is facilitated by a variety of membrane transport proteins, each with specificity for a particular class of molecule, e.g. sugars. Trans - port proteins fall mainly into two major classes: channel proteins and carrier proteins. Channel proteins form aqueous pores in the membrane, which open and close under the regulation of intracellular signals, e.g. G-proteins, to allow the flux of solutes (usually inorganic ions) of specific size and charge. Transport through ion channels is always passive, and ion flow through an open channel depends only on the ion concentration gradi -

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Basic structure and function of cells 10.e1 CHaPTER 1 Mitochondrial ribosomes are smaller and quite distinct from those of the rest of the cell in that they (and mitochondrial nucleic acids) resemble those of bacteria. This similarity underpins the theory that mitochondrial ancestors were oxygen-utilizing bacteria that existed in a symbiotic relationship with eukaryotic cells unable to metabolize the oxygen produced by early plants. As mitochondria are formed only from previously existing ones, it follows that all mitochondria in the body are descended from those in the cytoplasm of the fertilized ovum.

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Cell structure 11 CHaPTER 1 among signalling molecules in having no specific receptor protein; it acts directly on intracellular enzymes of the response pathway. Receptor proteins There are some 20 different families of receptor proteins, each with several isoforms responding to different ligands. The great majority of these receptors are transmembrane proteins. Members of each family share structural features that indicate either shared ligand-binding char - acteristics in the extracellular domain or shared signal transduction properties in the cytoplasmic domain, or both. There is little relation - ship either between the nature of a ligand and the family of receptor proteins to which it binds and activates, or the signal transduction strategies by which an intracellular response is achieved. The same ligand may activate fundamentally different types of receptor in differ - ent cell types. Cell surface receptor proteins are generally grouped according to their linkage to one of three intracellular systems: ion channel-linked receptors; G-protein coupled receptors; and receptors that link to enzyme systems. Other receptors do not fit neatly into any of these categories. All the known G-protein coupled receptors belong to a structural group of proteins that pass through the membrane seven times in a series of serpentine loops. These receptors are thus known as seven-pass transmembrane receptors or, because the transmembrane regions are formed from α-helical domains, as seven-helix receptors. The best known of this large group of phylogenetically ancient receptors are the odorant-binding proteins of the olfactory system; the light- sensitive receptor protein, rhodopsin; and many of the receptors for clinically useful drugs. A comprehensive list of receptor proteins, their activating ligands and examples of the resultant biological function is given in Pollard and Earnshaw (2008). Intracellular signalling A wide variety of small molecules carry signals within cells, conveying the signal from its source (e.g. activated plasma membrane receptor) to its target (e.g. the nucleus). These second messengers convey signals as fluctuations in local concentration, according to rates of synthesis and degradation by specific enzymes (e.g. cyclases involved in cyclic nucle - otide (cAMP, cGMP) synthesis), or, in the case of calcium, according to the activities of calcium channels and pumps. Other, lipidic, second inside the cell unless they first bind to a plasma membrane receptor protein. Ligands are mainly proteins (usually glycoproteins), polypep - tides or highly charged biogenic amines. They include: classic peptide hormones of the endocrine system; cytokines, which are mainly of haemopoietic cell origin and involved in inflammatory responses and tissue remodelling (e.g. the interferons, interleukins, tumour necrosis factor, leukaemia inhibitory factor); and polypeptide growth factors (e.g. the epidermal growth factor superfamily, nerve growth factor, platelet-derived growth factor, the fibroblast growth factor family, trans - forming growth factor beta and the insulin-like growth factors). Polypeptide growth factors are multifunctional molecules with more widespread actions and cellular sources than their names suggest. They and their receptors are commonly mutated or aberrantly expressed in certain cancers. The cancer-causing gene variant is termed a transform - ing oncogene and the normal (wild-type) version of the gene is a cel - lular oncogene or proto-oncogene. The activated receptor acts as a transducer to generate intracellular signals, which are either small dif- fusible second messengers (e.g. calcium, cyclic adenosine monophos - phate or the plasma membrane lipid-soluble diacylglycerol), or larger protein complexes that amplify and relay the signal to target control systems. Some signals are hydrophobic and able to cross the plasma mem - brane freely. Classic examples are the steroid hormones, thyroid hor - mones, retinoids and vitamin D. Steroids, for instance, enter cells non-selectively, but elicit a specific response only in those target cells that express specific cytoplasmic or nuclear receptors. Light stimuli also cross the plasma membranes of photoreceptor cells and interact intra - cellularly, at least in rod cells, with membrane-bound photosensitive receptor proteins. Hydrophobic ligands are transported in the blood stream or interstitial fluids, generally bound to carrier proteins, and they often have a longer half-life and longer-lasting effects on their targets than do water-soluble ligands. A separate group of signalling molecules able to cross the plasma membrane freely is typified by the gas, nitric oxide. The principal target of short-range nitric oxide signalling is smooth muscle, which relaxes in response. Nitric oxide is released from vascular endothelium as a result of the action of autonomic nerves that supply the vessel wall causing local relaxation of smooth muscle and dilation of vessels. This mechanism is responsible for penile erection. Nitric oxide is unusual Fig . 1 .7 The different modes of cell–cell signalling . A Endocrine B Paracrine C Autocrine D Synaptic E Neurocrine F Contact-dependentEndocrine cell A Different hormonesTarget cell BReceptor Y Target cell ABlood streamEndocrine cell B Receptor X Target cellsSignalling cell Membrane receptor Hormone or growth factorTarget cellSynapse Neurotransmitter Cell bodyAxonNeurone Distant target cellNeuroendocrinecellStimulus Blood vessel Membrane-bound signal moleculeSignalling cell Target cellShort-range signalling molecule Neuropeptide or amine

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BaSIC STR uCTuRE aNd fu NCTION Of CEllS 12 SECTION 1 are microfilaments (7 nm thick), microtubules (25 nm thick) and inter - mediate filaments (10 nm thick). Other important components are proteins that bind to the principal filamentous types to assemble or disassemble them, regulate their stability or generate movement. These include actin-binding proteins such as myosin, which in some cells can assemble into thick filaments, and microtubule-associated proteins. Pathologies involving cytoskeletal abnormalities include ciliopathies (resulting from the abnormal assembly and function of centrioles, basal bodies and cilia); neurodegenerative diseases (a consequence of defec- tive anterograde transport of neurotransmitters along microtubules in axons); and sterility (determined by defective or absent microtubule- associated dynein in axonemes, e.g. Kartagener’s syndrome). Actin filaments (microfilaments) Actin filaments are flexible filaments, 7 nm thick ( Fig. 1.8). Within most cell types, actin constitutes the most abundant protein and in some motile cells its concentration may exceed 200 µM (10 mg protein per ml cytoplasm). The filaments are formed by the ATP-dependent polymerization of actin monomer (with a molecular mass of 43 kDa) into a characteristic string of beads in which the subunits are arranged in a linear tight helix with a distance of 13 subunits between turns (Dominguez 2010). The polymerized filamentous form is termed F-actin (fibrillar actin) and the unpolymerized monomeric form is known as G-actin (globular actin). Each monomer has an asymmetric structure. When monomers polymerize, they confer a defined polarity on the filament: the plus or barbed end favours monomer addition, and the minus or pointed end favours monomer dissociation. Treadmilling designates the simultaneous polymerization of an actin filament at one end and depolymerization at the other end to maintain its constant length. See Bray (2001) for further reading. actin-binding proteins A wide variety of actin-binding proteins are capable of modulating the form of actin within the cell. These interactions are fundamental to the messengers such as phosphatidylinositol, derive from membranes and may act within the membrane to generate downstream effects. For further consideration of the complexity of intracellular signalling path- ways, see Pollard and Earnshaw (2008). Cytoskeleton The cytoskeleton is a three-dimensional network of filamentous intra - cellular proteins of different shapes, sizes and composition distributed throughout the cytoplasm. It provides mechanical support, maintains cell shape and rigidity, and enables cells to adopt highly asymmetric or irregular profiles. It plays an important part in establishing structural polarity and different functional domains within a cell. It also provides mechanical support for permanent projections from the cell surface (see below), including persistent microvilli and cilia, and transient proc - esses, such as the thin finger-like protrusions called filopodia (0.1– 0.3 µm) and lamellipodia (0.1–0.2 µm). Filopodia consist of parallel bundles of actin filaments and have a role in cell migration, wound healing and neurite growth. The protrusive thin and broad lamellipo - dia, found at the leading edge of a motile cell, contain a branched network of actin filaments. The cytoskeleton restricts specific structures to particular cellular locations. For example, the Golgi apparatus is near the nucleus and endoplasmic reticulum, and mitochondria are near sites of energy requirement. In addition, the cytoskeleton provides tracks for intracel- lular transport (e.g. shuttling vesicles and macromolecules, called cargoes, among cytoplasmic sites), the movement of chromosomes during cell division (mitosis and meiosis) or movement of the entire cell during embryonic morphogenesis or the chemotactic extravascular migration of leukocytes during homing. Examples of highly developed and specialized functions of the cytoskeleton include the contraction of the sarcomere in striated muscle cells and the bending of the axoneme of cilia and flagella. The catalogue of cytoskeletal structural proteins is extensive and still increasing. The major filamentous structures found in non-muscle cells Fig . 1 .8 Structural and molecular features of cytoskeletal components . A, The actin filament (F-actin) is a 7 nm thick polymer chain of ATP-bound G-actin monomers . F-actin consists of a barbed (plus) end, the initiation site of F-actin, and a pointed (minus) end, the dissociation site of F-actin . F-actin can be severed and capped at the barbed end by gelsolin . B, The microtubule is a 25 nm diameter polymer of GTP-bound α-tubulin and GTP-bound β-tubulin dimers . The dimer assembles at the plus end and depolymerizes at the minus end . A linear chain of α-tubulin/β-tubulin dimers is called a protofilament . In the end-on (top view), a microtubule displays 13 concentrically arranged tubulin subunits . C, Tetrameric complexes of intermediate filament subunits associate laterally to form a unit length filament consisting of eight tetramers . Additional unit length filaments anneal longitudinally and generate a mature 10 nm thick intermediate filament . Tetramer Unit length filament Intermediate filament Intermediate filament Microtubule Actin filament C B A10 nm thick25 nm in diameter 7 nm thick Top view: 13 concentric tubulinsProtofilamentMinus end Severed actin filament Capped barbed endGelsolin Pointed endPlus end Barbed endTubulin dimer Monomer GTPGTP GTPG-actin–ATPβ-tubulin α-tubulin

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Basic structure and function of cells 12.e1 CHaPTER 1 Septins are emerging as a novel cytoskeletal member because of their filamentous organization and association with actin filaments and microtubules. They are guanosine triphosphate (GTP)-binding proteins that form hetero-oligomeric complexes (see Mostowy and Cossart (2012) for additional information). This polarity can be visualized in negatively stained images by allow- ing F-actin to react with fragments containing the active head region of myosin. Myosins bind to filamentous actin at an angle to give the appearance of a series of arrowheads pointing towards the minus end of the filament, with the barbs pointing towards the plus end. It involves the addition of ATP-bound G-actin monomers at the barbed end (fast-growing plus end) and removal of ADP-bound G-actin at the pointed end (slow-growing minus end). Actin filaments grow or shrink by addition or loss of G-actin monomer at both ends. Essentially, actin polymerization in vitro proceeds in three steps: nucleation (aggre - gation of G-actin monomers into a 3–4-monomer aggregate), elonga - tion (addition of G-actin monomers to the aggregate) and a dynamic steady state (treadmilling). Specific toxins (e.g. cytochalasins, phalloi - dins and lantrunculins) bind to actin and affect its polymerization. Cytochalasin D blocks the addition of new G-actin monomers to the barbed end of F-actin; phalloidin binds to the interface between G-actin monomers in F-actin, thus preventing depolymerization; and lantrun- culin binds to G-actin monomers, blocking their addition to an actin filament.

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Cell structure 13 CHaPTER 1 organization of cytoplasm and to cell shape. The actin cytoskeleton is organized as closely packed parallel arrays of actin filaments forming bundles or cables, or loosely packed criss-crossed actin filaments forming networks (Fig. 1.9A). Actin-binding proteins hold together bundles and networks of actin filaments. Actin-binding proteins can be grouped into G-actin (monomer) binding proteins and F-actin (polymer) capping, cross-linking and severing proteins. Actin-binding proteins may have more than one function. Capping proteins bind to the ends of the actin filament either to stabilize an actin filament or to promote its disassembly (see Fig. 1.8). Cross-linking or bundling proteins tie actin filaments together in longitudinal arrays to form bundles, cables or core structures. The bundles may be closely packed in microvilli and filopodia, where paral - lel filaments are tied tightly together to form stiff bundles orientated in the same direction. Cross-linking proteins of the microvillus actin bundle core include fimbrin and villin. Other actin-bundling proteins form rather looser bundles of fila - ments that run antiparallel to each other with respect to their plus and minus ends. They include myosin II, which can form cross-links with ATP-dependent motor activity, and cause adjacent actin filaments to slide on each other in the striated muscle sarcomere, and either change the shape of cells or (if the actin bundles are anchored into the cell Fig . 1 .9 The cytoskeleton . A, An immunofluorescence micrograph of α-actin microfilaments (green) in human airway smooth muscle cells in culture . The actin-binding protein, vinculin (red), is localized at the ends of actin filament bundles; nuclei are blue . B, An immunofluorescence micrograph of keratin intermediate filaments (green) in human keratinocytes in culture . Desmosome junctions are labelled with antibody against desmoplakin (red) . Nuclei are stained blue (Hoechst) . C, An electron micrograph of human nerve showing microtubules (small, hollow structures in cross-section, long arrow) in a transverse section of an unmyelinated axon (A), engulfed by a Schwann cell (S) . Neuronal intermediate filaments (neurofilaments) are the solid, electron-dense profiles, also in transverse section (short arrow) . (A, Courtesy of Dr T Nguyen, Professor J Ward, Dr SJ Hirst, King’s College London . B, Courtesy of Prof . Dr WW Franke, German Cancer Research Centre, Heidelberg . C, Courtesy of Dr Bart Wagner, Histopathology Department, Sheffield Teaching Hospitals, UK .) A B CSA SAmembrane at both ends), maintain a degree of active rigidity. Filamin interconnects adjacent actin filaments to produce loose filamentous gel-like networks composed of randomly orientated F-actin. F-actin can branch. The assembly of branched filamentous actin networks involves a complex of seven actin-related proteins 2/3 (Arp2/3) that is structurally similar to the barbed end of actin. See Rotty et al (2013) for further reading. Branched actin generated by the Arp2/3 protein complex localizes at the leading edge of migrating cells, lamellipodia and phagosomes (required for the capture by endocytosis and phagocytosis of particles and foreign pathogens by immune cells). Formin can elongate pre- existing actin filaments by removing capping proteins at the barbed end. Other classes of actin-binding protein link the actin cytoskeleton to the plasma membrane either directly or indirectly through a variety of membrane-associated proteins. The latter may also create links via transmembrane proteins to the extracellular matrix. Best known of these is the family of spectrin-like molecules, which can bind to actin and also to each other and to various membrane-associated proteins to create supportive networks beneath the plasma membrane. Tetrameres of spectrin α and β chains line the intracellular side of the plasma membrane of erythrocytes and maintain their integrity by their associa - tion with short actin filaments at either end of the tetramer. Class V myosins are unconventional motor proteins transporting cargoes (such as vesicles and organelles) along actin filaments. Class I myosins are involved in membrane dynamics and actin organi - zation at the cell cortex, thus affecting cell migration, endocytosis, pinocytosis and phagocytosis. Tropomyosin, an important regulatory protein of muscle fibres, is also present in non-muscle cells, where its function may be primarily to stabilize actin filaments against depolymerization. Myosins, the motor proteins The myosin family of microfilaments is often classified within a distinct category of motor proteins. Myosin proteins have a globular head region consisting of a heavy and a light chain. The heavy chain bears an α-helical tail of varying length. The head has an ATPase activity and can bind to and move along actin filaments – the basis for myosin function as a motor protein. The best-known class is myosin II, which occurs in muscle and in many non-muscle cells. Its molecules have two heads and two tails, intertwined to form a long rod. The rods can bind to each other to form long, thick filaments, as seen in striated and smooth muscle fibres and myoepithelial cells. Myosin II molecules can also assemble into smaller groups, especially dimers, which can cross- link individual actin microfilaments in stress fibres and other F-actin arrays. The ATP-dependent sliding of myosin on actin forms the basis for muscle contraction and the extension of microfilament bundles, as seen in cellular motility or in the contraction of the ring of actin and myosin around the cleavage furrow of dividing cells. There are a number of known subtypes of myosin II; they assemble in different ways and have different dynamic properties. In skeletal muscle the myosin mol - ecules form bipolar filaments 15 nm thick. Because these filaments have a symmetric antiparallel arrangement of subunits, the midpoint is bare of head regions. In smooth muscle the molecules form thicker, flattened bundles and are orientated in random directions on either face of the bundle. These arrangements have important consequences for the con - tractile force characteristics of the different types of muscle cell. Related molecules include the myosin I subfamily of single-headed molecules with tails of varying length. Functions of myosin I include the movements of membranes in endocytosis, filopodial formation in neuronal growth cones, actin–actin sliding and attachment of actin to membranes as seen in microvilli. As indicated above, molecular motors of the myosin V family are implicated in the movements of cargoes on actin filaments. So, for example, myosin Va transports vesicles along F-actin tracks in a similar manner to kinesin and cytoplasmic dynein- related cargo transport along microtubules. Each class of motor protein has different properties, but during cargo trafficking they often function together in a coordinated fashion. (See Hammer 3rd and Sellers (2012) for further reading on class V myosins.) Other thin filaments A heterogeneous group of filamentous structures with diameters of 2–4 nm occurs in various cells. The two most widely studied forms, titin and nebulin, constitute around 13% of the total protein of skeletal muscle. They are amongst the largest known molecules and have subunit weights of around 10 6; native molecules are about 1 µm in length. Their repetitive bead-like structure gives them elastic properties that are important for the effective functioning of muscle, and possibly for other cells.

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Basic structure and function of cells 13.e1 CHaPTER 1 Profilin and thymosin β4 are G-actin binding proteins. Profilin binds to G-actin bound to ATP; it inhibits addition of G-actin to the slow- growing (pointed) end of F-actin but enables the fast-growing (barbed) end to grow faster and then dissociates from the actin filament. In addi - tion, profilin participates in the conversion of ADP back to the ATP–G- actin bound form. Thymosin β4 binds to the ATP–G-actin bound form, preventing polymerization by sequestering ATP–G-actin into a reserve pool. Members of the F-actin capping protein family are heterodimers consisting of an α subunit (CP α) and a β subunit (CP β) that cap the barbed end of actin filaments within all eukaryotic cells. Gelsolin has a dual role: it severs F-actin and caps the newly formed barbed end, blocking further filament elongation. Fascin is an additional cross-linking protein. Villin is also a severing protein, causing the disassembly of actin filaments and the collapse of the microvillus.In the presence of activated nucleation promotion factors, such as Wiskott–Aldrich syndrome protein (WASP) and WASP family verprolin-homologous protein (WAVE, also known as SCAR), the Arp2/3 protein complex binds to the side of an existing actin filament (mother fila - ment) and initiates the formation of a branching actin daughter fila - ment at a 70° angle relative to the mother filament utilizing G-actin delivered to the Arp2/3 complex site. Spectrin-related molecules are present in many other cells. For instance, fodrin is found in neurones and dystrophin occurs in muscle cells, linking the contractile apparatus with the extracellular matrix via integral membrane proteins. Proteins such as ankyrin (which also binds actin directly), vinculin, talin, zyxin and paxillin connect actin-binding proteins to integral plasma membrane proteins such as integrins (directly or indirectly), and thence to focal adhesions (consisting of a bundle of actin filaments attached to a portion of a plasma membrane linked to the extracellular matrix).

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BaSIC STR uCTuRE aNd fu NCTION Of CEllS 14 SECTION 1 microtubules for considerable distances, thus enabling selective target - ing of materials within the cell. Such movements occur in both direc - tions along microtubules. Kinesin-dependent motion is usually towards the plus ends of microtubules, e.g. from the cell body towards the axon terminals in neurones, and away from the centrosome in other cells. Conversely, dynein-related movements are in the opposite direction, i.e. to the minus ends of microtubules. Dyneins also form the arms of peripheral microtubules in cilia and flagella, where they make dynamic cross-bridges to adjacent microtubule pairs. When these tethered dyneins try to move, the resulting shearing forces cause the axonemal array of microtubules to bend, generating ciliary and flagellar beating movements. Kinesins form a large and diverse family of related microtubule-stimulated ATPases. Some kinesins are motors that move cargo and others cause microtubule disassembly, whilst still others cross-link mitotic spindle microtubules to push the two centriolar poles apart during mitotic prophase. See Bray (2001) for further reading. Centrioles, centrosomes and basal bodies Centrioles are microtubular cylinders 0.2 µm in diameter and 0.4 µm long (Fig. 1.10). They are formed by a ring of nine microtubule triplets linked by a number of other proteins. At least two centrioles occur in all animal cells that are capable of mitotic division (eggs, which undergo meiosis instead of mitosis, lack centrioles). See Gönczy (2012) for further reading on the structure and assembly of the centriole. They usually lie close together, at right angles or, most usually, at an oblique angle to each other (an arrangement often termed a diplosome), within the centrosome, a densely filamentous region of cytoplasm at the centre of the cell. The centrosome is the major microtubule-organizing centre of most cells; it is the site at which new microtubules are formed and the mitotic spindle is generated during cell division. Centriole biogen - esis is a complex process. At the beginning of the S phase (DNA replica - tion phase) of the cell cycle (see below), a new daughter centriole forms at right angles to each separated maternal centriole. Each mother– daughter pair forms one pole of the next mitotic spindle, and the daughter centriole becomes fully mature only as the progeny cells are about to enter the next mitosis. Because centrosomes are microtubule- organizing centres, they lie at the centre of a network of microtubules, all of which have their minus ends proximal to the centrosome. The microtubule-organizing centre contains complexes of γ-tubulin that nucleate microtubule polymerization at the minus ends of micro- tubules. Basal bodies are microtubule-organizing centres that are closely related to centrioles, and are believed to be derived from them. They are located at the bases of cilia and flagella, which they anchor to the cell surface. The outer microtubule doublets of the axoneme of cilia and flagella originate from two of the microtubules in each triplet of the basal body. microtubule-based transport of cargoes The transport of cargoes along microtubules via the motor proteins kinesin and cytoplasmic dynein respectively is the means by which neurotransmitters are delivered along axons to neuronal synapses Microtubules Microtubules are polymers of tubulin with the form of hollow, rela- tively rigid cylinders, approximately 25 nm in diameter and of varying length (up to 70 µm in spermatozoan flagella). They are present in most cell types, being particularly abundant in neurones, leukocytes and blood platelets. Microtubules are the predominant constituents of the mitotic spindles of dividing cells and also form part of the axoneme of cilia, flagella and centrioles. Microtubules consist of tubulin dimers and microtubule-associated proteins. There are two major classes of tubulin: α- and β-tubulins. Before microtubule assembly, tubulins are associated as dimers with a combined molecular mass of 100 kDa (50 kDa each). Each protein subunit is approximately 5 nm across and is arranged along the long axis in straight rows of alternating α- and β-tubulins, forming protofila- ments (see Fig. 1.8). Typically, 13 protofilaments (the number can vary between 1 1 and 16) associate in a ring to form the wall of a hollow cylindrical microtubule. Each longitudinal row is slightly out of align - ment with its neighbour, so that a spiral pattern of alternating α and β subunits appears when the microtubule is viewed from the side. There is a dynamic equilibrium between the dimers and assembled microtu - bules: dimeric asymmetry creates polarity ( α-tubulins are all orientated towards the minus end, β-tubulins towards the plus end). Tubulin is added preferentially to the plus end; the minus end is relatively slow-growing. Microtubules frequently grow and shrink at a rapid and con - stant rate, a phenomenon known as dynamic instability, in which growing tubules can undergo a ‘catastrophe’, abruptly shifting from net growth to rapid shrinkage. The primary determinant of whether micro - tubules grow or shrink is the rate of GTP hydrolysis. Tubulins are GTP-binding proteins; microtubule growth is accompanied by hydrolysis of GTP, which may regulate the dynamic behaviour of the tubules. Micro - tubule growth is initiated at specific sites, the microtubule-organizing centres, of which the best known are centrosomes (from which most cellular microtubules polymerize) and the centriole-derived basal bodies (from which cilia grow). Microtubule-organizing centres include a specialized tubulin isoform known as γ-tubulin that is essential for the nucleation of microtubule growth. Various drugs (e.g. colcemid, vinblastine, griseofulvin, nocodazole) cause microtubule depolymerization by binding the soluble tubulin dimers and so shifting the equilibrium towards the unpolymerized state. Microtubule disassembly causes a wide variety of effects, including the inhibition of cell division by disruption of the mitotic spindle. Conversely, the drug paclitaxel (taxol) is a microtubule depolymeriza - tion inhibitor because it stabilizes microtubules and promotes abnor - mal microtubule assembly. Although this can cause a peripheral neuropathy, paclitaxel is widely used as an effective chemotherapeutic agent in the treatment of breast and ovarian cancer. microtubule-associated proteins Various proteins that can bind to assembled tubulins may be concerned with structural properties or associated with motility. One important class of microtubule-associated proteins (MAPs) consists of proteins that associate with the plus ends of microtubules. They regulate the dynamic instability of microtubules as well as interactions with other cellular substructures. Structural MAPs form cross-bridges between adja - cent microtubules or between microtubules and other structures such as intermediate filaments, mitochondria and the plasma membrane. Microtubule-associated proteins found in neurones include: MAPs 1A and 1B, which are present in neuronal dendrites and axons; MAPs 2A and 2B, found chiefly in dendrites; and tau, found only in axons. MAP 4 is the major microtubule-associated protein in many other cell types. Structural microtubule-associated proteins are implicated in microtu - bule formation, maintenance and disassembly, and are therefore of considerable significance in cell morphogenesis, mitotic division, and the maintenance and modulation of cell shape. Transport-associated microtubule-associated proteins are found in situations in which move - ment occurs over the surfaces of microtubules, e.g. cargo transport, bending of cilia and flagella, and some movements of mitotic spindles. They include a large family of motor proteins, the best known of which are the dyneins and kinesins. Another protein, dynamin, is involved in endocytosis. The kinetochore proteins assemble at the chromosomal centromere during mitosis and meiosis. They attach (and thus fasten chromosomes) to spindle microtubules; some of the kinetochore pro - teins are responsible for chromosomal movements in mitotic and meiotic anaphase. All of these microtubule-associated proteins bind to microtubules and either actively slide along their surfaces or promote microtubule assembly or disassembly. Kinesins and dyneins can simultaneously attach to membranes such as transport vesicles and convey them along Fig . 1 .10 A duplicated pair of centrioles in a human carcinoma specimen . Each centriole pair consists of a mother and daughter, orientated approximately at right angles to each other so that one is sectioned transversely (T) and the other longitudinally (L) . The transversely sectioned centrioles are seen as rings of microtubule triplets (arrow) . (Courtesy of Dr Bart Wagner, Histopathology Department, Sheffield Teaching Hospitals, UK .) T LT

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Basic structure and function of cells 14.e1 CHaPTER 1 The association of membrane vesicles with dynein motors means that certain cytomembranes (including the Golgi apparatus) concen- trate near the centrosome. This is convenient because the microtubules provide a means of targeting Golgi vesicular products to different parts of the cell.

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Cell structure 15 CHaPTER 1 sion. Of the different classes of intermediate filaments, keratin (cyto - keratin) proteins are found in epithelia, where keratin filaments are always composed of equal ratios of type I (acidic) and type II (basic to neutral) keratins to form heteropolymers. About 20 types of each of the acidic and basic/neutral keratin proteins are known. For further reading on keratins in normal and diseased epithelia, see Pan et al (2012). Within the epidermis, expression of keratin heteropolymers changes as keratinocytes mature during their transition from basal to superficial layers. Genetic abnormalities of keratins are known to affect the mechanical stability of epithelia. For example, the disease epidermolysis bullosa simplex is caused by lysis of epidermal basal cells and blistering of the skin after mechanical trauma. Defects in genes encoding keratins 5 and 14 produce cytoskeletal instability leading to cellular fragility in the basal cells of the epidermis. When keratins 1 and 10 are affected, cells in the spinous (prickle) cell layer of the epidermis lyse, and this produces the intraepidermal blistering of epidermolytic hyperkeratosis. See Porter and Lane (2003) for further reading. Type III intermediate filament proteins, including vimentin, desmin, glial fibrillary acidic protein and peripherin, form homopolymer inter - mediate filaments. Vimentin is expressed in mesenchyme-derived cells of connective tissue and some ectodermal cells during early develop - ment; desmins in muscle cells; glial fibrillary acidic protein in glial cells; and peripherin in peripheral axons. Type IV intermediate fila - ments include neurofilaments, nestin, syncoilin and α-internexin. Neu- rofilaments are a major cytoskeletal element in neurones, particularly in axons (see Fig. 1.9C), where they are the dominant protein. Neuro - filaments (NF) are heteropolymers of low (NF–L), medium (NF–M) and high (NF–H) molecular weight (the NF–L form is always present in combination with either NF–M or NF–H forms). Abnormal accumu - lations of neurofilaments (neurofibrillary tangles) are characteristic features of a number of neuropathological conditions. Nestin resem - bles a neurofilament protein, which forms intermediate filaments in neurectodermal stem cells in particular. The type V intermediate fila - ment group includes the nuclear lamins A, lamin B1 and lamin B2 lining the inner surface of the nuclear envelope of all nucleated cells. Lamin C is a splice variant of lamin A. Lamins provide a mechanical framework for the nucleus and act as attachment sites for a number of proteins that organize chromatin at the periphery of the nucleus. They are unusual in that they form an irregular anastomosing network of filaments rather than linear bundles. See Burke and Stewart (2013) for further reading. Nucleus The nucleus (see Figs 1.1–1.2) is generally the largest intracellular struc - ture and is usually spherical or ellipsoid in shape, with a diameter of 3–10 µm. Conventional histological stains, such as haematoxylin or toluidine blue, detect the acidic components (phosphate groups) of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) in cells and tissue sections. DNA and RNA molecules are said to be basophilic because of the binding affinity of their negatively charged phosphate groups to basic dyes such as haematoxylin. A specific stain for DNA is the Feulgen reaction. Nuclear envelope The nucleus is surrounded by the nuclear envelope, which consists of an inner nuclear membrane (INM) and an outer nuclear membrane (ONM), separated by a 40–50 nm perinuclear space that is spanned by nuclear pore complexes (NPCs). The perinuclear space is continuous with the lumen of the endoplasmic reticulum. The ONM has multiple connections with the endoplasmic reticulum, with which it shares its membrane protein components. The INM contains its own specific integral membrane proteins (lamin B receptor and emerin, both pro - viding binding sites for chromatin bridging proteins). A mutation in the gene encoding emerin causes X-linked Emery–Dreifuss muscular dystrophy (EDMD), characterized by skeletal muscle wasting and cardiomyopathy. The nuclear lamina, a 15–20 nm thick, protein-dense meshwork, is associated with the inner face of the INM. The major components of the nuclear lamina are lamins, the type V intermediate filament proteins consisting of A-type and B-type classes. The nuclear lamina reinforces the nuclear membrane mechanically, determines the shape of the nucleus and provides a binding site for a range of proteins that anchor chromatin to the cytoskeleton. Nuclear lamin A, with over 350 mutations, is the most mutated protein linked to human disease. These are referred to as laminopathies, characterized by nuclear structural abnormalities that cause structurally weakened nuclei, leading to mechanical damage. Lamin A mutations cause a (anterograde axonal transport) and membrane-bound vesicles are returned for recycling to the neuronal soma (retrograde axonal trans - port) (p. 45). In addition to anterograde and retrograde motor proteins, the assembly and maintenance of all cilia and flagella involve the par - ticipation of non-membrane-bound macromolecular protein com - plexes called intraflagellar transport (IFT) particles. IFT particles localize along the polarized microtubules of the axoneme, beneath the ciliary and flagellar membrane. IFT particles consist of two protein subcom - plexes: IFT-A (with a role in returning cargoes from the tip of the axoneme to the cell body) and IFT-B (with a role in delivering cargoes from the cell body to the tip of the axoneme). For further reading, see Scholey (2008) and Hao and Scholey (2009). During ciliogenesis, IFT requires the anterograde kinesin-2 motor and the retrograde IFT-dynein motor to transport IFT particles–cargo complexes in opposite directions along the microtubules, from the basal body to the tip of the ciliary axoneme and back again (intraciliary transport). IFT is not just restricted to microtubules of cilia and flagella. During spermatid development, IFT particles–motor protein–cargo complexes appear to utilize microtubules of the manchette, a transient microtubule-containing structure, to deliver tubulin dimers and other proteins by intramanchette transport during the development of the spermatid tail (Kierszenbaum et al 201 1). IFT also occurs along the modified cilium of photoreceptor cells of the retina. Mutations in IFT proteins lead to the absence of cilia and are lethal during embryogen- esis. Ciliopathies, many related to the defective sensory and/or mechan - ical function of cilia, include retinal degeneration, polycystic kidney disease, Bardet–Biedl syndrome, Jeune asphyxiating thoracic dystrophy, respiratory disease and defective determination of the left–right axis. The seven-protein complex designated BBSome (for Bardet–Biedl syn- drome, an obesity/retinopathy ciliopathy) is a component of the basal body and participates in the formation of the primary cilium by regulat - ing the export and/or import of ciliary proteins. The transport of the BBSome up and down and round about in cilia occurs in association with anterograde IFT-B and retrograde IFT-A particles. For further reading on the BBSome, see Jin and Nachury (2009). For further reading on ciliogenesis, see Baldari and Rosenbaum (2010). Intermediate filaments Intermediate filaments are about 10 nm thick and are formed by a heterogeneous group of filamentous proteins. In contrast to actin fila - ments and microtubules, which are assembled from globular proteins with nucleotide-binding and hydrolysing activity, intermediate fila - ments consist of filamentous monomers lacking enzymatic activity. Intermediate filament proteins assemble to form linear filaments in a three-step process. First, a pair of intermediate filament protein sub - units, each consisting of a central α-helical rod domain of about 310 amino acids flanked by head and tail non- α-helical domains of varia- ble size, form a parallel dimer through their central α-helical rod domains coiled around each other. The variability of intermediate fila - ment protein subunits resides in the length and amino-acid sequence of the head and tail domains, thought to be involved in regulating the interaction of intermediate filaments with other proteins. Second, a tetrameric unit is formed by two antiparallel half-staggered coiled dimers. Third, eight tetramers associate laterally to form a 16 nm thick unit length filament (ULF). Individual ULFs join end to end to form short filaments that continue growing longitudinally by annealing to other ULFs and existing filaments. Filament elongation is followed by internal compaction leading to the 30 nm thick intermediate filament (see Fig. 1.8). The tight association of dimers, tetramers and ULFs pro - vides intermediate filaments with high tensile strength and resistance to stretching, compression, twisting and bending forces. In contrast to actin filaments and microtubules, intermediate filaments are non- polar (because of the antiparallel alignment of the initial tetramers) and do not bind nucleo tides (as in G-actin and tubulin dimers), and ULFs anneal end to end to each other (in contrast to the polarized F-actin and microtubules, with one end, the plus end, growing faster than the other end, the minus end). See Herrmann et al (2007) for further reading. Intermediate filaments are found in different cell types and are often present in large numbers, either to provide structural strength where it is needed (see Fig. 1.9B,C) or to provide scaffolding for the attachment of other structures. Intermediate filaments form extensive cytoplasmic networks extending from cage-like perinuclear arrangements to the cell surface. Intermediate filaments of different molecular classes are char - acteristic of particular tissues or states of maturity and are therefore important indicators of the origins of cells or degrees of differentiation, as well as being of considerable value in histopathology. Intermediate filament proteins have been classified into five distinct types on the basis of their primary structure and tissue-specific expres -

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Basic structure and function of cells 15.e1 CHaPTER 1 A-type lamins include lamin A (interacting with emerin), lamin C, lamin C2 and lamin AΔ10 encoded by a single gene (LMNA). Lamin A and lamin C are the major A-type lamins expressed in somatic cells, whereas lamin C2 is expressed in testis. B-type lamins include lamin B1 and lamin B2 (expressed in somatic cells), and testis-specific lamin B3. Lamin B1 is encoded by the LMNB1 gene; lamin B2 is encoded by the LMNB2 gene.

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BaSIC STR uCTuRE aNd fu NCTION Of CEllS 16 SECTION 1 permeable to small molecules, ions and proteins up to about 17 kDa. See Raices and D’Angelo (2012) for further reading on nuclear pore complex composition. Most proteins that enter the nucleus do so as complexes with specific transport receptor proteins known as import - ins. Importins shuttle back and forth between the nucleus and cyto - plasm. Binding of the cargo to the importin requires a short sequence of amino acids known as a nuclear localization sequence (NLS), and can either be direct or take place via an adapter protein. Interactions of the importin with components of the nuclear pore move it, together with its cargo, through the pore by an energy-independent process. A complementary cycle functions in export of proteins and RNA mol-ecules from the nucleus to the cytoplasm using transport receptors known as exportins. A small GTPase called Ras-related nuclear protein (Ran) regulates the import and export of proteins across the nuclear envelope. For further reading on the Ran pathway and exportins/importins, see Clarke and Zhang (2008) and Raices and D’Angelo (2012). Chromatin DNA is organized within the nucleus in a DNA–protein complex known as chromatin. The protein constituents of chromatin are the histones and the non-histone proteins. Non-histone proteins are an extremely heterogeneous group that includes structural proteins, DNA and RNA polymerases, and gene regulatory proteins. Histones are the most abun - dant group of proteins in chromatin, primarily responsible for the packaging of chromosomal DNA into its primary level of organization, the nucleosome. There are four core histone proteins – H2A, H2B, H3 and H4 – which combine in equal ratios to form a compact octameric nucleosome core. A fifth histone, H1, is involved in further compaction of the chromatin. The DNA molecule (one per chromosome) winds twice around each nucleosome core, taking up 165 nucleotide pairs. This packaging organizes the DNA into a chromatin fibre 1 1 nm in diameter, and imparts to this form of chromatin the electron micro - scopic appearance of beads on a string, in which each bead is separated by a variable length of DNA, typically about 35 nucleotide pairs long. The nucleosome core region and one of the linker regions constitute the nucleosome proper, which is typically about 200 nucleotide pairs in length. However, chromatin rarely exists in this simple form and is usually packaged further into a 30 nm thick fibre, involving a single H1 histone per nucleosome, which interacts with both DNA and protein to impose a higher order of nucleosome packing. Usually, 30 nm thick fibres are further coiled or folded into larger domains. Individual domains are believed to decondense and extend during active transcrip- tion. In a typical interphase nucleus, euchromatin (nuclear regions that appear pale in appropriately stained tissue sections, or relatively electron-lucent in electron micrographs; see Fig. 1.2) is likely to consist mainly of 30 nm fibres and loops, and contains the transcriptionally active genes. Transcriptionally active cells, such as most neurones, have nuclei that are predominantly euchromatic. See Luger et al (2012) for further reading on the nucleosome and chromatin structure. Heterochromatin (nuclear regions that appear dark in appropriately stained tissue sections or electron-dense in electron micrographs) is characteristically located mainly around the periphery of the nucleus, except over the nuclear pores (see Fig. 1.1 1A), and adjacent to the nucleolus (see Fig. 1.2). It is a relatively compacted form of chromatin in which the histone proteins carry a specific set of post-translational modifications, including methylation at characteristic residues. This facilitates the binding of specific heterochromatin-associated proteins. Heterochromatin includes non-coding regions of DNA, such as centro - meric regions, which are known as constitutive heterochromatin. DNA becomes transcriptionally inactive in some cells as they differentiate during development or cell maturation, and contributes to heterochro- matin; it is known as facultative heterochromatin. The inactive X chro- mosome in females is an example of facultative heterochromatin and can be identified in the light microscope as the deeply staining Barr body often located near the nuclear periphery or a drumstick extension of a nuclear lobe of a mature multilobed neutrophil leukocyte. In transcriptionally inactive cells, chromatin is predominantly in the condensed, heterochromatic state, and may comprise as much as 90% of the total. Examples of such cells are mature neutrophil leukocytes (in which the condensed chromatin is present in a multilobular, densely staining nucleus) and the highly condensed nuclei of orthochromatic erythroblasts (late-stage erythrocyte precursors). In most mature cells, a mixture of the two occurs, indicating that only a proportion of the DNA is being transcribed. A particular instance of this is seen in the B lymphocyte-derived plasma cell, in which much of the chromatin is in the condensed condition and is arranged in regular masses around the perimeter of the nucleus, producing the so-called ‘clock-face’ nucleus (see Figs 4.6, 4.12). Although this cell is actively transcribing, much of surprisingly wide range of diseases, from progeria to various dystro - phies, including an autosomal dominant form of EDMD. A truncated farnesylated form of lamin A, referred to as progerin, leads to defects in cell proliferation and DNA damage of mesenchymal stem cells and vascular smooth muscle cells. Affected patients display cardiovascular disease and die at an early age. Mice lacking lamin B1 and lamin B2 survive until birth; however, neuronal development is compromised when lamin B1 or lamin B2 is absent. Overexpression of lamin B1 is associated with autosomal dominant leukodystrophy characterized by gradual demyelination in the central nervous system. See Worman (2012) and Burke and Stewart (2013) for additional reading on lamins and laminopathies. Condensed chromatin (heterochromatin) tends to aggregate near the nuclear envelope during interphase. At the end of mitotic and meiotic prophase (see below), the lamin filaments disassemble by phosphorylation, causing the nuclear membranes to vesiculate and disperse into the endoplasmic reticulum. During the final stages of mitosis (telophase), proteins of the nuclear periphery, including lamins, associate with the surface of the chromosomes, providing docking sites for membrane vesicles. Fusion of these vesicles reconstitutes the nuclear envelope, including the nuclear lamina, following lamin dephosphor - ylation. See Simon and Wilson (201 1) for further reading on the nucleoskeleton. The transport of molecules between the nucleus and the cytoplasm occurs via specialized nuclear pore structures that perforate the nuclear membrane (Fig. 1.1 1A). They act as highly selective directional molecu - lar filters, permitting proteins such as histones and gene regulatory proteins (which are synthesized in the cytoplasm but function in the nucleus) to enter the nucleus, and molecules that are synthesized in the nucleus but destined for the cytoplasm (e.g. ribosomal subunits, trans - fer RNAs and messenger RNAs) to leave the nucleus. Ultrastructurally, nuclear pores appear as disc-like structures with an outer diameter of 130 nm and an inner pore with an effective diameter for free diffusion of 9 nm ( Fig. 1.1 1B). The nuclear envelope of an active cell contains up to 4000 such pores. The nuclear pore complex has an octagonal symmetry and is formed by an assembly of more than 50 proteins, the nucleoporins. The inner and outer nuclear membranes fuse around the pore complex (see Fig. 1.1 1A). Nuclear pores are freely Fig . 1 .11 A, The nuclear envelope with nuclear pores (arrows) in transverse section, showing the continuity between the inner and outer phospholipid layers of the envelope on either side of the pore . The fine ‘membrane’ appearing to span the pore is formed by proteins of the pore complex . Note that the chromatin is less condensed in the region of nuclear pores . Abbreviations: N, nucleus; C, cytoplasm . B, Nuclear pores seen ‘en face ’ as spherical structures (arrows) in a tangential section through the nuclear envelope . The appearance of the envelope varies in electron density as the plane of section passes through different regions of the curved double membrane, which is interrupted at intervals by pores through the envelope (see also Fig . 1 .1) . The surrounding cytoplasm with ribosomes is less electron-dense . Human tissues . (Courtesy of Dr Bart Wagner, Histopathology Department, Sheffield Teaching Hospitals, UK .) N CA B

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Cell structure 17 CHaPTER 1 easily seen during metaphase, although prophase chromosomes can be used for more detailed analyses. Lymphocytes separated from blood samples, or cells taken from other tissues, are used as a source of chromosomes. Diagnosis of fetal chromosome patterns is generally carried out on samples of amniotic fluid containing fetal cells aspirated from the uterus by amniocentesis, or on a small piece of chorionic villus tissue removed from the placenta. Whatever their origin, the cells are cultured in vitro and stimulated to divide by treatment with agents that stimulate cell division. Mitosis is interrupted at metaphase with spindle inhibitors. The chromosomes are dispersed by first causing the cells to swell in a hypotonic solution, then the cells are gently fixed and mechanically ruptured on a slide to spread the chromosomes. They are subsequently stained in various ways to allow the identification of individual chromosomes by size, shape and distribution of stain (Fig. 1.12). General techniques show the obvious landmarks, e.g. lengths of arms and positions of constrictions. Banding techniques demonstrate differential staining patterns, characteristic for each chromosome type. Fluorescence staining with quinacrine mustard and related compounds produces Q bands, and Giemsa staining (after treatment that partially denatures the chromatin) gives G bands ( Fig. 1.12A). Other less widely used methods include: reverse Giemsa stain - ing, in which the light and dark areas are reversed (R bands); the stain - ing of constitutive heterochromatin with silver salts (C-banding); and T-banding to stain the ends (telomeres) of chromosomes. Collectively, these methods permit the classification of chromosomes into num - bered autosomal pairs in order of decreasing size, from 1 to 22, plus the sex chromosomes. A summary of the major classes of chromosome is given in Table 1.1. Methodological advances in banding techniques improved the re - cognition of abnormal chromosome patterns. The use of in situ hybridi- zation with fluorescent DNA probes specific for each chromosome ( Fig. 1.12B) permits the identification of even very small abnormalities. Nucleolus Nucleoli are a prominent feature of an interphase nucleus (see Fig. 1.2). They are the site of most of the synthesis of ribosomal RNA (rRNA) and assembly of ribosome subunits. Nucleoli organize at the end of mitosis its protein synthesis is of a single immunoglobulin type, and conse - quently much of its genome is in an inactive state. During mitosis, the chromatin is further reorganized and condensed to form the much-shortened chromosomes characteristic of metaphase. This shortening is achieved through further levels of close packing of the chromatin. The condensed chromosomes are stabilized by protein complexes known as condensins. Progressive folding of the chromo - somal DNA by interactions with specific proteins can reduce 5 cm of chromosomal DNA by 10,000-fold, to a length of 5 µm in the mitotic chromosome. Chromosomes and telomeres The nuclear DNA of eukaryotic cells is organized into linear units called chromosomes. The DNA in a normal human diploid cell contains 6 × 109 nucleotide pairs organized in the form of 46 chromosomes (44 autosomes and 2 sex chromosomes). The largest human chromosome (number 1) contains 2.5 × 108 nucleotide pairs, and the smallest (the Y chromosome) 5 × 107 nucleotide pairs. Each chromosomal DNA molecule contains a number of specialized nucleotide sequences that are associated with its maintenance. One is the centromeric DNA region. During mitosis, a disc-shaped structure composed of a complex array of proteins, the kinetochore, forms as a substructure at the centromeric region of DNA to which kinetochore microtubules of the spindle attach. Another region, the telomere, defines the end of each chromosomal DNA molecule. Telomeres consist of hundreds of repeats of the nucleotide sequence (TTAGGG) n. The very ends of the chromosomes cannot be replicated by the same DNA polymerase as the rest of the chromosome, and are maintained by a specific enzyme called telomerase, which contains an RNA subunit acting as the template for lengthening the TTAGGG repeats. See Nandakumar and Cech (2013) for further reading on the recruitment of telomerase to telomeres. Thus telomerase is a specialized type of polymerase known as a reverse transcriptase that turns sequences in RNA back into DNA. The number of tandem repeats of the telomeric DNA sequence varies. The telomere appears to shorten with successive cell divisions because telomerase activity reduces or is absent in dif- ferentiated cells with a finite lifespan. In mammals, telomerase is active in the germ-cell lineage and in stem cells, but its expression in somatic cells may lead to or prompt cancer. A lack of telomere maintenance determines the shrinking of telomeres in proliferating cells to the point when cells stop dividing, a condition known as replicative senescence. See Sahin and DePinho (2012) for further reading on telomeres and progressive DNA damage. The role of the telomere in ageing and cell senescence is further discussed at the end of this chapter. Karyotypes: classification of human chromosomes A number of genetic abnormalities can be directly related to the chro - mosomal pattern. The characterization or karyotyping of chromosome number and structure is therefore of considerable diagnostic impor - tance. The identifying features of individual chromosomes are most Fig . 1 .12 Chromosomes from normal males, arranged as karyotypes . A, G-banded preparation . B, Preparation stained by multiplex fluorescence in situ hybridization to identify each chromosome . (Courtesy of Dr Denise Sheer, Cancer Research UK .) 1 6 13 19 20 21 22 X Y14 15 16 17 187 8 9 10 11 122 3 4 5 A 1 6 7 8 9 10 11 12 18 17 16 15 14 13 19 20 21 22 X Y2 3 4 5 BTable 1.1 Summary of the major classes of chromosome Group Features 1–3 (A) Large metacentric chromosomes 4–5 (B) Large submetacentric chromosomes 6–12 + X (C) Metacentrics of medium size 13–15 (D) Medium-sized acrocentrics with satellites 16–18 (E) Shorter metacentrics (16) or submetacentrics (17,18) 19–20 (F) Shortest metacentrics 21–22 + Y (G) Short acrocentrics; 21, 22 with satellites, Y without

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Basic structure and function of cells 17.e1 CHaPTER 1 Telomerase has been associated with ageing and cell senescence because a gradual loss of telomeres may lead to tissue atrophy, stem cell depletion and deficient tissue repair or regeneration. Mutations causing loss of function of telomerase or the RNA-containing template have been associated with dyskeratosis congenita (characterized by abnormal skin pigmentation, nail dystrophy and mucosal leukoplasia), aplastic anaemia and pulmonary fibrosis.

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BaSIC STR uCTuRE aNd fu NCTION Of CEllS 18 SECTION 1 certain tumour suppressor genes (e.g. the gene mutated in retinoblas - toma, Rb) block the cycle in G 1. DNA synthesis (replication of the genome) occurs during S phase, at the end of which the DNA content of the cell has doubled. During G 2, the cell prepares for division; this period ends with the onset of chromosome condensation and break - down of the nuclear envelope. The times taken for S, G 2 and M are similar for most cell types, and occupy 6–8, 2–4 and 1–2 hours respec - tively. In contrast, the duration of G 1 shows considerable variation, sometimes ranging from less than 2 hours in rapidly dividing cells to more than 100 hours, within the same tissue. The passage of a cell through the cell cycle is controlled by proteins in the cytoplasm: cyclins and cyclin-dependent kinases (Cdks; Fig 1.13). Cyclins include G 1 cyclins (D cyclins), S-phase cyclins (cyclins E and A) and mitotic cyclins (B cyclins). Cdks, protein kinases, which are activated by binding of a cyclin subunit, include G 1 Cdk (Cdk4), an S-phase Cdk (Cdk2) and an M-phase Cdk (Cdk1). Cell cycle progres - sion is driven in part by changes in the activity of Cdks. Each cell cycle stage is characterized by the activity of one or more Cdk–cyclin pairs. Transitions between cell cycle stages are triggered by highly specific proteolysis by the 26S proteasome of the cyclins and other key components. To give one example, the transition from G 2 to mitosis is driven by activation of Cdk1 by its partners, the A- and B-type cyclins; the char - acteristic changes in cellular structure that occur as cells enter mitosis are largely driven by phosphorylation of proteins by active Cdk1-cyclin A and Cdk1-cyclin B. Cells exit from mitosis when an E3 ubiquitin ligase, the anaphase promoting complex, also called cyclosome (APC/C), marks the cyclins for destruction. In addition, APC/C prompts the degradation of the mitotic cyclin B and the destruction of cohesins, thus allowing sister chromatids to separate. There are important checkpoints in the cell cycle (see Fig. 1.13). Checkpoint 1 requires G 1 cyclins to bind to their corresponding Cdks to signal the cell to prepare for DNA synthesis. S-phase promoting factor (SPF; cyclin A bound to Cdk2) enters the nucleus to stimulate DNA synthesis. Checkpoint 2 requires M-phase promoting factor (mitotic cyclin B bound to M-phase Cdk1) to trigger the assembly of the mitotic spindle, breakdown of the nuclear envelope, arrest of gene transcription and condensation of chromosomes. During metaphase of mitosis, M-phase promoting factor activates APC/C, which determines the breakdown of cohesins, the protein complex holding sister chroma - tids together. Then, at anaphase, separated chromatids move to the opposite poles of the spindle. Finally, B cyclins are destroyed following and consist of repeated clusters of ribosomal DNA (rDNA) genes and processing molecules responsible for producing ribosome subunits. The initial step of the assembly of a ribosome subunit starts with the tran - scription of rDNA genes by RNA polymerase I. The rDNA genes, arranged in tandem repeats called nucleolar organizing regions (NORs), are located on acrocentric chromosomes. There are five pairs of acro - centric chromosomes in humans. The initial 47S rRNA precursor tran - script is cleaved to form the mature 28S, 18S and 5.8S rRNAs, assembled with the 5S rRNA (synthesized by RNA polymerase III outside the nucleolus) and coupled to small nucleolar ribonucleoproteins and other non-ribosomal proteins to form 60S (containing 28S rRNA, 5.8S rRNA and 5S rRNA) and 40S (containing 18S rRNA) preribosome sub - units. These are then exported to the cytoplasm across nuclear pores as mature ribosome subunits. About 726 human nucleolar proteins have been identified by protein purification and mass spectrometry. For further reading on nucleolar functions, see Boisvert et al (2007). Ribosomal biogenesis occurs in distinct subregions of the nucleolus, visualized by electron microscopy. The three nucleolar subregions are fibrillar centres (FCs), dense fibrillar components (DFCs) and granular components (GCs). Transcription of the rDNA repeats takes place at the FC-DFC boundary; pools of RNA polymerase I reside in the FC region; processing of transcripts and coupling to small nucleolar ribo - nucleoproteins take place in DFC; and the assembly of ribosome sub - units is completed in the GC region. The nucleolus is disassembled when cells enter mitosis and tran - scription becomes inactive. It reforms after nuclear envelope reorganiza - tion in telophase, in a process associated with the onset of transcription in nucleolar organizing centres on each specific chromosome, and becomes functional during the G 1 phase of the cell cycle. An adequate pool of ribosome subunits during cell growth and cell division requires steady nucleolar activity to support protein synthesis. Several DNA helicases, a conserved group of enzymes that unwind DNA, accumulate in the nucleolus under specific conditions such as Bloom’s syndrome (an autosomal recessive disorder characterized by growth deficiency, immunodeficiency and a predisposition to cancer) and Werner’s syn - drome (an autosomal recessive condition characterized by the early appearance of various age-related diseases). CELL DIVISION AND THE CELL CYCLE During prenatal development, most cells undergo repeated division (see Video 1.1) as the body grows in size and complexity. As cells mature, they differentiate structurally and functionally. Some cells, such as neurones, lose the ability to divide. Others may persist throughout the lifetime of the individual as replication-competent stem cells, e.g. cells in the haemopoietic tissue of bone marrow. Many stem cells divide infrequently, but give rise to daughter cells that undergo repeated cycles of mitotic division as transit (or transient) amplifying cells. Their divi - sions may occur in rapid succession, as in cell lineages with a short lifespan and similarly fast turnover and replacement time. Transit amplifying cells are all destined to differentiate and ultimately to die and be replaced, unlike the population of parental stem cells, which self-renews. Patterns and rates of cell division within tissues vary considerably. In many epithelia, such as the crypts between intestinal villi, the replace - ment of damaged or ageing cells by division of stem cells can be rapid. Rates of cell division may also vary according to demand, as occurs in the healing of wounded skin, in which cell proliferation increases to a peak and then returns to the normal replacement level. The rate of cell division is tightly coupled to the demand for growth and replacement. Where this coupling is faulty, tissues either fail to grow or replace their cells, or they can overgrow, producing neoplasms. The cell cycle is an ordered sequence of events, culminating in cell growth and division to produce two daughter cells. It generally lasts a minimum of 12 hours, but in most adult tissues can be considerably longer, and is divided into four distinct phases, which are known as G 1 (for gap 1), S (for DNA synthesis), G 2 (for gap 2) and M (for mitosis). The combination of G 1, S and G 2 phases is known as interphase. M is the mitotic phase, which is further divided into four phases (see below). G1 is the period when cells respond to growth factors directing the cell to initiate another cycle; once made, this decision is irreversible. It is also the phase in which most of the molecular machinery required to complete another cell cycle is generated. Centrosomes duplicate during S phase in preparation for mitosis. Cells that retain the capacity for proliferation, but which are no longer dividing, have entered a phase called G 0 and are described as quiescent even though they may be quite active physiologically. Growth factors can stimulate quiescent cells to leave G 0 and re-enter the cell cycle, whereas the proteins encoded by Fig . 1 .13 The cell cycle consists of an interphase (G 1 phase, S phase and G2 phase) followed by mitosis . The cyclin D/Cdk4 complex assembles at the beginning of G 1; the cyclin E/Cdk2 complex assembles near the end of G 1 as the cell is preparing to cross checkpoint 1 to start DNA synthesis (during S phase) . The cyclin A/Cdk2 complex assembles as DNA synthesis starts . Completion of G 2 is indicated by the assembled cyclin A/ Cdk1 complex . A cell crosses checkpoint 2 to initiate mitosis when the cyclin B/Cdk1 complex assembles . The cyclin B/Cdk1 complex is degraded by the 26S proteasome and an assembled cyclin D/Cdk4 marks the start of the G 1 phase of a new cell cycle . For details, see text . (Modified with permission from Kierszenbaum AL, Tres LL . Histology and Cell Biology: An Introduction to Pathology . 3rd ed, Philadelphia: Elsevier, Saunders; 2011 .)Cyclin ACyclin D Cyclin ECyclin A Cdk2 Cdk4 Cdk2Cdk1 Mitosis SCyclin BCdk1G2 G1Checkpoint 1Checkpoint 2

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Basic structure and function of cells 18.e1 CHaPTER 1 The targets for proteolysis are marked for destruction by E3 ubiquitin ligases, which decorate them with polymers of the small protein ubiq - uitin, a sign for recognition by the 26S proteasome.

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Cell division and the cell cycle 19 CHaPTER 1 their attachment to ubiquitin, targeting them for destruction by the 26S proteasome. As G 1 starts, cyclins D, bound to Cdk4, start preparation for a new cell cycle. Quality control checkpoint 2 operates to delay cell-cycle progression when DNA has been damaged by radiation or chemical mutagens. Cells with checkpoint defects, such as loss of the protein p53, which is a major negative control element in the division cycle of all cells, are commonly associated with the development of malignancy. An example is Li Fraumeni syndrome, where a defective p53 gene leads to a high frequency of cancer in affected individuals. In cells, p53 protein binds DNA and stimulates another gene to produce p21 protein, which inter - acts with Cdk2 to prevent S-phase promoting activity. When mutant p53 can no longer bind DNA to stimulate production of p21 to stop DNA synthesis, cells acquire oncogenic properties. The p53 gene is an example of a tumour suppressor gene. For further reading on p53 muta- tions and cancer, see Muller and Vousden (2013). Mitosis and meiosis Mitosis is the process that results in the distribution of identical copies of the parent cell genome to the two daughter somatic cells. In meiosis, the divisions immediately before the final production of gametes halve the number of chromosomes to the haploid number, so that at fertiliza - tion the diploid number is restored. Moreover, meiosis includes a phase in which exchange of genetic material occurs between homologous chromosomes. This allows a rearrangement of genes to take place, which means that the daughter cells differ from the parental cell in both their precise genetic sequence and their haploid state. Mitosis and meiosis are alike in many respects, and differ principally in chromo - somal behaviour during the early stages of cell division. In meiosis, two divisions occur in succession, without an intervening S phase. Meiosis I is distinct from mitosis, whereas meiosis II is more like mitosis. Mitosis New DNA is synthesized during the S phase of the cell cycle interphase. This means that the amount of DNA in diploid cells has doubled to the tetraploid value by the onset of mitosis, although the chromosome number is still diploid. During mitosis, this amount is halved between the two daughter cells, so that DNA quantity and chromosome number are diploid in both cells. The cellular changes that achieve this distribu - tion are conventionally divided into four phases called prophase, meta - phase, anaphase and telophase ( Figs 1.14–1.15, Video 1.1). Prophase During prophase, the strands of chromatin, which are highly extended during interphase, shorten, thicken and resolve themselves into recog - nizable chromosomes. Each chromosome is made up of duplicate chro - matids (the products of DNA replication) joined at their centromeres. Outside the nucleus, the two centriole pairs begin to separate, and move towards opposite poles of the cell. Parallel microtubules are assembled between them to create the mitotic spindle, and others radiate to form the microtubule asters, which come to form the spindle poles or mitotic centre. As prophase proceeds, the nucleoli disappear, and the nuclear envelope suddenly disintegrates to release the chromosomes, an event that marks the end of prophase. Prometaphase–metaphase As the nuclear envelope disappears, the spindle microtubules extend into the central region of the cell, attaching to the chromosomes, which subsequently move towards the equator of the spindle (prometaphase). The spindle consists of kinetochore microtubules attached to the kine - tochore, a multiprotein structure assembled at the centromeric DNA region, and polar microtubules, which are not attached to chromo - somes but instead overlap with each other at the centre of the cell. The grouping of chromosomes at the spindle equator is called the meta - phase or equatorial plate. The chromosomes, attached at their centro - meres, appear to be arranged in a ring when viewed from either pole of the cell, or to lie linearly across this plane when viewed from above. Cytoplasmic movements during late metaphase effect the approxi- mately equal distribution of mitochondria and other cell structures around the cell periphery. anaphase By the end of metaphase every chromosome consists of a pair of sister chromatids attached to opposing spindle poles by bundles of microtu - bules associated with the kinetochore. The onset of anaphase begins with the proteolytic cleavage by the enzyme separase of a key subunit of protein complexes known as cohesins. The latter hold the replicated sister chromatids together to resist separation even when exposed to Fig . 1 .14 The stages in mitosis, including the appearance and distribution of the chromosomes . Prophase Nuclear membrane Centromere Two sister chromatidsattached at centromereMicrotubules of spindleCentriole centre of aster (or spindle pole) Prometaphase Spindle pole Nuclear membrane vesiclesMicrotubule Metaphase Cell equator Anaphase Chromatids pulled toward pole of spindle as their microtubules shorten Telophase Nuclear membrane reformsChromosomes decondense and detach from microtubules Cytokinesis Nuclear membraneCentriole Actin–myosin belt microtubule-dependent pulling forces. Proteolytic cleavage releases the cohesion between sister chromatids, which then move towards opposite spindle poles while the microtubule bundles attached to the kineto - chores shorten and move polewards. At the end of anaphase the sister chromatids are grouped at either end of the cell, and both clusters are

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BaSIC STR uCTuRE aNd fu NCTION Of CEllS 20 SECTION 1 diploid in number. An infolding of the cell equator begins, deepening during telophase as the cleavage furrow. Telophase During telophase the nuclear envelopes reform, beginning with the association of membranous vesicles with the surface of the chromo - somes. Later, after the vesicles have fused and the nuclear envelope is complete, the chromosomes decondense and the nucleoli reform. At the same time, cytoplasmic division, which usually begins in early anaphase, continues until the new cells separate, each with its derived nucleus. The spindle remnant now disintegrates. While the cleavage furrow is active, a peripheral band or belt of actin and myosin appears in the constricting zone; contraction of this band is responsible for furrow formation. Failure of disjunction of chromatids, so that sister chromatids pass to the same pole, may sometimes occur. Of the two new cells, one will have more, and the other fewer, chromosomes than the diploid number. Exposure to ionizing radiation promotes non-disjunction and may, by chromosomal damage, inhibit mitosis altogether. A typical symptom of radiation exposure is the failure of rapidly dividing epithelia to replace lost cells, with consequent ulceration of the skin and mucous mem- branes. Mitosis can also be disrupted by chemical agents, particularly vinblastine, paclitaxel (taxol) and their derivatives. These compounds either disassemble spindle microtubules or interfere with their dynam - ics, so that mitosis is arrested in metaphase. Meiosis There are two consecutive cell divisions during meiosis: meiosis I and meiosis II ( Fig. 1.16). Details of this process differ at a cellular level for male and female lineages.Fig . 1 .15 Immunofluorescence images of stages in mitosis in human carcinoma cells in culture . A, Metaphase, with spindle microtubules (green), the microtubule- stabilizing protein (HURP; red) and chromosomal DNA (blue) . B, Anaphase, with spindle microtubules (green), the central spindle (Aurora-B kinase, red) and segregated chromosomes (blue) . C, Late anaphase, with spindle microtubules (green), the central spindle (Plk1 kinase, red, appearing yellow where co-localized with microtubule protein) and segregated chromosomes (blue) . (Courtesy of Dr Herman Silljé, Max-Planck- Institut für Biochemie, Martinsried, Germany .) A B C Fig . 1 .16 The stages in meiosis, depicted by two pairs of maternal and paternal homologues (dark and pale colours) . DNA and chromosome complement changes and exchange of genetic information between homologues are indicated . Pairing of paternal and maternal homologuesBA Events preceding meiosis B Meiotic prophase C Meiosis I D Meiosis IIPremeiotic S phaseCentromere Meiotic prophasePaired sister centromeres Meiosis I Leptotene Zygotene Pachytene Diplotene DiakinesisAa bA a bB Metaphase I Anaphase I Prophase II Metaphase IIA aB bA a bBChiasmata Meiosis I Meiosis II Interphase (no S phase)A bB a A aB b Anaphase II Haploid gametes

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Cell polarity and domains 21 CHaPTER 1 equatorial plane of the spindle. The centromeres of each pair of sister chromatids function as a single unit, facing a single spindle pole. Homologous chromosomes are pulled towards opposite spindle poles, but are held paired at the spindle midzone by chiasmata. Errors in chromosome segregation (known as non-disjunction) lead to the pro- duction of aneuploid progeny. Most human aneuploid embryos are non-viable and this is the major cause of fetal loss (spontaneous abor - tion), particularly during the first trimester of pregnancy in humans. The most common form of viable aneuploid progeny in humans is Down’s syndrome (trisomy for chromosome 21), which exhibits a dra- matic increase with maternal age. Anaphase and telophase I Anaphase I of meiosis begins with the release of cohesion between the arms of sister chromatids, much as it does during mitosis. As position - ing of bivalent pairs is random, assortment of maternal and paternal chromosomes in each telophase nucleus is also random. Critically, sister centromeres, and thus chromatids, do not separate during ana- phase I. During meiosis I, cytoplasmic division occurs by specialized mecha - nisms. In females, the division is highly asymmetric, producing one egg and one tiny cell known as a polar body. In males, the process results in production of spermatocytes that remain joined by small cytoplas - mic bridges. meiosis II Meiosis II commences after only a short interval during which no DNA synthesis occurs. The centromeres of sister chromatids remain paired, but rotate so that each one can face an opposite spindle pole. Onset of anaphase II is triggered by loss of cohesion between the centromeres, as it is in mitosis. This second division is more like mitosis, in that chromatids separate during anaphase, but, unlike mitosis, the separat - ing chromatids are genetically different (the result of genetic recombi - nation). Cytoplasmic division also occurs and thus, in the male, four haploid cells, interconnected by cytoplasmic bridges, result from meiosis I and II. CELL POLARITY AND DOMAINS Epithelia are organized into sheets or glandular structures with very different environments on either side. These cells actively transfer mac- romolecules and ions between the two surfaces and are thus polarized in structure and function. In polarized cells, particularly in epithelia, the cell is generally subdivided into domains that reflect the polariza - tion of activities within it. The free surface, e.g. that facing the intestinal lumen or airway, is the apical surface, and its adjacent cytoplasm is the apical cell domain. This is where the cell interfaces with a specific body compartment (or, in the case of the epidermis, with the outside world). The apical surface is specialized to act as a barrier, restricting access of substances from this compartment to the rest of the body. Specific components are selectively absorbed from, or added to, the external compartment by the active processes, respectively, of active transport and endocytosis inwardly or exocytosis and secretion outwardly. The apical surface is often covered with small protrusions of the cell surface, microvilli, which increase the surface area, particularly for absorption. The surface of the cell opposite to the apical surface is the basal surface, with its associated basolateral cell domain. In a single-layered epithelium, this surface faces the basal lamina. The remaining surfaces are known as the lateral cell surfaces. In many instances, the lateral and basal surfaces perform similar functions and the cellular domain is termed the basolateral domain. Cells actively transport substances, such as digested nutrients from the intestinal lumen or endocrine secretions, across their basal (or basolateral) surfaces into the subjacent connective tissue matrix and the blood capillaries within it. Dissolved non-polar gases (oxygen and carbon dioxide) diffuse freely between the cell and the blood stream across the basolateral surface. Apical and basolateral surfaces are separated by a tight intercellular seal, the tight junction (occluding junction, zonula adherens), which prevents the passage of even small ions through the space between adjacent cells and thus maintains the difference between environments on either side of the epithelium. Cell surface apical differentiations The surfaces of many different types of cell are specialized to form structures that project from the surface. These projections may permit meiosis I Prophase I Meiotic prophase I is a long and complex phase that differs consider - ably from mitotic prophase and is customarily divided into five sub - stages, called leptotene, zygotene, pachytene, diplotene and diakinesis. There are three distinctive features of male meiotic prophase that are not seen during mitotic prophase: the pairing, or synapse, of homolo - gous chromosomes of paternal and maternal origin to form bivalent structures; the organization of nucleoli by autosomal bivalents; and significant non-ribosomal RNA synthesis by autosomal bivalents (in contrast to the transcriptional inactivity of the XY chromosomal pair) (see Tres 2005). In the female, meiotic prophase I starts during fetal gonadogenesis, is arrested at the diplotene stage and resumes at puberty. In the male, meiosis starts at puberty. Leptotene stage During leptotene, homologous chromosomes (maternal and paternal copies of the same chromosome), replicated in a preceding S phase and each consisting of sister chromatids joined at the centromere (see above), locate one another within the nucleus, and the process of genetic recombination is initiated. Cytologically, chro - mosomes begin to condense, appearing as individual threads that are attached via their telomeres to the nuclear envelope. They often show characteristic beading throughout their length. Zygotene stage During zygotene, the homologous chromosomes initiate pairing or synapsis, during which they become intimately asso - ciated with one another. Synapsis may begin near the telomeres at the inner surface of the nuclear membrane, and during this stage the tel - omeres often cluster to one side of the nucleus (a stage known as the bouquet because the chromosomes resemble a bouquet of flowers). The pairs of synapsed homologues, also known as bivalents, are linked together by a tripartite ribbon, the synaptonemal complex, which con - sists of two lateral dense elements and a central, less dense, linear element. The sex chromosomes also start to synapse during zygotene. In males, with distinct X and Y chromosomes, synapsis involves a region of shared DNA sequence known as the pseudoautosomal region. The XY bivalent adopts a special condensed structure, known as the sex vesicle, which becomes associated later at pachytene with migratory nucleolar masses originating in the autosomal bivalents. Chromosome behaviour in meiosis is intimately linked with the process of genetic recombination. This begins during leptotene, as homologous chromosomes first locate one another at a distance. Syn - apsis, stabilized by the synaptonemal complex, facilitates recombina - tion, as sites of genetic exchange are turned into specialized structures known as chiasmata, which are topological crossing-over points that hold homologous chromosomes together. Pachytene stage When synapsis is complete for all chromosomes, the cell is said to be in pachytene. Each bivalent looks like a single thick structure, but is actually two pairs of sister chromatids held together by the synaptonemal complex. Genetic recombination between non-sister chromatids is completed at this point, with sites where it has occurred (usually one per chromosome arm) appearing as recombination nodules in the centre of the synaptonemal complex. Diplotene stage During diplotene, the synaptonemal complex disas - sembles and pairs of homologous chromosomes, now much shortened, separate, except where crossing over has occurred (chiasmata). This process is called disjunction. At least one chiasma forms between each homologous pair, exchanging maternal and paternal sequences; up to five have been observed. In the ovaries, primary oocytes become diplo - tene by the fifth month in utero and each remains at this stage until the period before ovulation (up to 50 years). Diakinesis Diakinesis is the prometaphase of the first meiotic divi- sion. The chromosomes, still as bivalents, become even shorter and thicker. They gradually attach to the spindle and become aligned at a metaphase plate. In eggs, the spindle forms without centrosomes. Microtubules first nucleate and are stabilized near the chromosomes; the action of various motor molecules eventually sorts them into a bipolar spindle. Perhaps surprisingly, this spindle is as efficient a machine for chromosome segregation as the spindle of mitotic cells with centrosomes at the poles. Metaphase I Metaphase I resembles mitotic metaphase, except that the bodies attach - ing to the spindle microtubules are bivalents, not single chromosomes. These become arranged so that the homologous pairs occupy the

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BaSIC STR uCTuRE aNd fu NCTION Of CEllS 22 SECTION 1 its distal region, called the transition zone. The continued elongation of the cilium requires the import and intraciliary transport of tubulin dimers to the distal tip by bidirectional motor-driven proteins of the intraflagellar transport complex. The constant length of cilia is maintained by a steady-state balance between tubulin turnover and addition of new tubulin dimers at the ciliary tip. Several filamentous structures are associated with the 9 + 2 doublet microtubule of the axoneme in the cilium or flagellum shaft, e.g. radial spokes extend inwards from the outer doublet microtubules towards the central pair, surrounded by an inner sheath (see Fig. 1.17). The outer doublet microtubules bear two rows of tangential dynein arms attached to the complete A subfibre of the doublet (consisting of 13 protofila - ments), which point towards the incomplete B subfibre of the adjacent doublet (consisting of 10–1 1 protofilaments). Adjacent doublets are also linked by thin nexin filaments. Tektins are scaffolding filamentous proteins extending along the axonemal microtubules. In motile cilia, arrays of dynein arms with ATPase activity cause outer microtubule doublets to move past one another, resulting in a large- scale bending motion. Microtubules do not change in length. Move - ments of cilia and flagella are broadly similar. In addition to the axoneme, spermatozoan flagella have outer dense fibres and a fibrous sheath surrounding the axoneme. Flagella move by rapid undulation, which passes from the attached to the free end. In human spermatozoa, there is an additional helical component to this motion. In cilia, the beating is planar but asymmetric. In the effective stroke, the cilium remains stiff except at the base, where it bends to produce an oar-like stroke. The recovery stroke follows, during which the bend passes from base to tip, returning the cilium to its initial position for the next cycle. The activity of groups of cilia is usually coordinated so that the bending of one is rapidly followed by the bending of the next and so on, movement of the cell itself (flagella), or of fluids across the apical cell surface (cilia), or increase the surface area available for absorption (microvilli). Infoldings of the basolateral plasma membrane also increase the area for transport across this surface of the cell. In most non-dividing epithelial cells, the centriole-derived basal body gives rise to a non-motile primary cilium, which has an important mechanosen - sory role. Cilia and flagella Cilia and flagella are motile, hair-like projections of the cell surface, which create currents in the surrounding fluid or movements of the cell to which they are attached, or both. There are two categories of cilia: single non-motile primary cilia and multiple motile cilia. Primary cilia are immotile but can detect physical and biochemical signals. Motile cilia are present in large numbers on the apical epithelial domain of the upper respiratory tract and oviducts, and beat in a wave-like motion to generate fluid movement. Cilia also occur, in modified form, at the dendritic endings of olfactory receptor cells, vestibular hair cells (kino - cilium), and the photoreceptor rods and cones of the retina. Flagella, with a primary function in cell locomotion, are found on single-cell eukaryotes and in spermatozoa, which each possess a single flagellum 70 µm long. A cilium or flagellum consists of a shaft (0.25 µm diameter) consti- tuting most of its length, a tapering tip and a basal body at its base, which lies within the surface cytoplasm of the cell ( Fig. 1.17). Other than at its base, the entire structure of the cilium is covered by plasma membrane. The core of the cilium is the axoneme, a cylinder of nine microtubule doublets that surrounds a central pair of single microtu - bules (see Fig. 1.17). Ciliogenesis of primary cilia and motile cilia involves distinct steps. A centriole-derived basal body migrates to the apical cell domain and axonemal microtubule doublets emerge from Fig . 1 .17 A, The structure of a cilium shown in longitudinal (left) and transverse (right) section . A and B are subfibres of the peripheral microtubule doublets (see text); the basal body is structurally similar to a centriole, but with microtubule triplets . B, The apical region of respiratory epithelial cells, showing the proximal parts of three cilia sectioned longitudinally, anchored into the cytoplasm by basal bodies (BB) . Other cilia project out of the plane of section and are cut transversely, showing the ‘9 + 2’ arrangement of microtubules . (B, With permission from Young B, Heath JW . Wheater’s Functional Histology . 4th ed . Edinburgh: Elsevier, Churchill Livingstone; 2000 .)Inner sheath Central microtubulesDynein ‘arms’ RootletA Microtubule doubletsNexin-linking protein Radial spokeAB Tubulin subunits Microtubule tripletsPlasma membrane Basal body B BBBB

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Basic structure and function of cells 22.e1 CHaPTER 1 As indicated on page 15, the IFT-B protein complex participates in intraciliary/intraflagellar anterograde transport of cargoes, a step essen- tial for the assembly and maintenance of cilia and flagella; the IFT-A protein complex is required for retrograde transport of cargoes to the cell body for turnover. The movement of IFT proteins along microtu - bules is catalysed by kinesin-2 (towards the ciliary tip; anterograde direction) and cytoplasmic dynein-2 motor proteins (towards the cell body; retrograde direction). A cargo includes axonemal components, ciliary/flagellar membrane proteins (including the BBSome) and ciliary signal transduction proteins.

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Cell polarity and domains 23 CHaPTER 1 resulting in long travelling waves of metachronal synchrony. These pass over the tissue surface in the same direction as the effective stroke. Ciliary motion is important in clearing mucus from airways, moving eggs along oviducts, and circulating cerebrospinal fluid in brain ventri - cles. In the node of the developing embryo, cilium-driven flow is essen - tial for determining left–right visceral asymmetry (developing patterning). Cilia also have a sensory function, determined by the pres - ence of receptor and channel proteins on the ciliary membrane. Primary cilia in the collecting ducts of the uriniferous tubule sense the flow of urine and also modulate duct morphogenesis. Cilia are essential for signalling through the hedgehog pathway, a mechanism involved in organizing the body plan, organogenesis and tumorigenesis in verte - brates. For additional reading on hedgehog signalling and primary cilia, see Briscoe and Thérond (2013). There is a group of genetic diseases in which cilia beat either inef - fectively or not at all, e.g. Kartagener’s immotile cilia syndrome. Affected cilia exhibit deficient function or a lack of dynein arms. Males are typi - cally sterile because of the loss of spermatozoan motility, and half have an alimentary tract that is a mirror image of the usual pattern ( situs inversus), i.e. it rotates in the opposite direction during early develop - ment. Defects in ciliary motility disrupt airway mucus clearance, leading to chronic sinusitis and bronchiectasis. Defects in sensory cilia deter - mine polycystic kidney disease, anosmia and retinal degeneration. Microvilli Microvilli are finger-like cell surface extensions usually 0.1 µm in diam - eter and up to 2 µm long ( Fig. 1.18). Microvilli are covered by plasma membrane and supported inter - nally by closely packed bundles of actin filaments linked by cross-bridges of the actin-bundling proteins, fascin and fimbrin. Other bridges composed of myosin I and calmodulin connect the filament bundles to the plasma membrane. At the tip of each microvillus, the free ends of microfilaments are inserted into a dense mass that includes the protein, villin. The actin filament bundles of microvilli are embed - ded in the apical cytoplasm amongst a meshwork of transversely running actin filaments stabilized by spectrin to form the terminal web, which is underlain by keratin intermediate filaments. The web is anchored laterally to the tight junctions and zonula adherens of the apical epithelial junctional complex. Myosin II and tropomyosin are also found in the terminal web, which may explain its contractile activity. Microvilli greatly increase the area of cell surface (up to 40 times), particularly at sites of active absorption. In the small intestine, they have a very thick cell coat or glycocalyx, which reflects the presence of integral membrane glycoproteins, including enzymes concerned with digestion and absorption. Irregular microvilli, filopodia, are also found on the surfaces of many types of cell, particularly free macrophages and fibro - blasts, where they may be associated with phagocytosis and cell motil - ity. For further reading on the cytoskeleton of microvilli, see Brown and McKnight (2010). Long and branching microvilli are called stereocilia, an early misno - mer, as they are not motile and lack microtubules. An appropriate name is stereovilli. They are found on cochlear and vestibular receptor cells, where they act as sensory transducers, and also in the absorptive epi - thelium of the epididymis. Intercellular junctions The basolateral region of the plasma membrane of epithelial cells estab - lishes junctions with adjacent cells and with structural components of the extracellular matrix. Intercellular junctions are resilient and dynamic, and prevent epithelial tissues from dissociating into their component cells. In adults, the epidermis withstands imposed deformations because of the interplay of two components of intercellular junctions, the junc - tional cytoskeleton and cell adhesion molecules ( Fig. 1.19). The estab- lishment and maintenance of cell polarity in an epithelial layer depends on two circumferential apical belts, the tight junctions and the zonulae adherentes, running in parallel to each other and associated with F-actin. These two belts control epithelial permeability and determine epithelial cell polarity. The apical cell domain resides above the belts; the basolateral cell domain resides below the belts. Desmosomes (maculae adherentes) are a third class of spot-like intercellular adhe - sion. In contrast to tight junctions and the zonulae adherentes, desmo - somes do not form belts and link instead to intermediate filaments. The hemidesmosome, anchoring epithelial cells to the basal lamina, also links to intermediate filaments. Gap junctions are unique: they provide direct connection between adjacent cells and are not linked to the cytoskeleton. Molecular aspects of cell adhesion molecules will be con- sidered first and then integrated with the junctional cytoskeleton to define specific structural and molecular aspects of different intercellular junctions. Cell adhesion molecules Cell adhesion molecules are transmembrane or membrane-anchored glycoproteins that bridge the intercellular space from the plasma mem- brane to form adhesive contacts. There are a number of molecular subgroups, which are broadly divisible on the basis of their dependence on calcium for function. Calcium-dependent cell adhesion molecules include cadherins and selectins. Calcium-independent cell adhesion molecules include the immunoglobulin-like superfamily of cell adhe - sion molecules (Ig-CAMs), including nectins, and integrins, the only cell adhesion molecules consisting of two subunits ( α and β subunits). Calcium-dependent cell adhesion molecules: cadherins and selectins Cadherins are single-pass transmembrane glycoproteins, with five heavily glycosylated calcium-binding external domains and an intra - cellular catenin-binding cytoplasmic tail. Catenins are intracellular proteins linking cadherins to F-actin in the belt-arranged zonula adhe - rens. The extracellular segment of cadherins participates in Ca2+-depend- ent homophilic trans-interactions in which a cadherin molecule on one cell binds to an identical cadherin molecule on an adjacent cell. After binding, cadherins cluster laterally ( cis-interaction) at cell–cell junc - tions to form a zipper-like structure that stabilizes tight adhesion between cells. Different cell types possess different members of the cadherin family, e.g. N-cadherins in nervous tissue, E-cadherins in epithelia, and P-cadherins in the placenta. Two further members of the cadherin family are the desmogleins and the desmocollins. Cadherins are present in macula adherens and desmosomes but not in tight junctions or hemidesmosomes (see below). Alterations in the expression of cadher- ins in the epidermis produce pathological conditions such as blisters and ulcerations. See Brieher and Yap (2013) for further reading on cadherins and their associated cytoskeleton. As with cadherins, selectins are Ca 2+-dependent. In contrast to cad - herins, selectins do not establish homophilic trans-interactions. Instead, they bind to carbohydrates and belong to the group of lectins. Each selectin has an extracellular carbohydrate recognition domain (CRD) with binding affinity to a specific oligosaccharide attached to a protein or lipid. The molecular configuration and binding affinity of the CRD to carbohydrate moieties is Ca 2+-dependent. Selectins participate in the homing of leukocytes circulating in blood towards tissues by Fig . 1 .18 Microvilli sectioned longitudinally in the striated border of an intestinal absorptive cell in a human duodenal biopsy specimen . Actin filaments fill the cores of the microvilli and insert into the apical cytoplasm . A prominent glycocalyx (formed by the extracellular domains of plasma membrane glycoproteins) is seen as a fuzzy coat at the tips of and between microvilli; it includes enzymes concerned with the final stages of digestion . (Courtesy of Dr Bart Wagner, Histopathology Department, Sheffield Teaching Hospitals, UK .)

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Basic structure and function of cells 23.e1 CHaPTER 1 When arranged in a regular parallel series, as typified by the absorp - tive surfaces of the epithelial enterocytes of the small intestine and the proximal convoluted tubule of the nephron of the kidneys, microvilli acquire a fuzzy appearance like the bristles of a paintbrush (the designa - tions brush border or striated border are used at the light microscope level). The cytoplasmic tail recruits proteins of the catenin complex: β-catenin is the first to be recruited and the cadherin– β-catenin complex rapidly recruits α-catenin; α-catenin binds directly to F-actin and coor - dinates the activity of actin nucleating proteins and actin binding part - ners (such as vinculin and α-actinin) to provide the dynamic forces to modulate cell–cell adhesion; p120-catenin binds to the cytoplasmic tail of cadherin and becomes a positive regulator of cadherin function.

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BaSIC STR uCTuRE aNd fu NCTION Of CEllS 24 SECTION 1 loops, a transmembrane segment and a cytoplasmic tail. The nectins and Necls consist of four and five members, respectively. These are present in the belt-like tight junctions and zonula adherens. The nectin–afadin complex initiates the formation of a zonula adherens and after cell–cell contacts are formed between adjacent cells, cadherins are recruited to these contact sites. Afadin and α-catenin interact with one another and also with F-actin through adaptor proteins. Integrins mediate cell–extracellular matrix and cell–cell interactions, and integrate extracellular signals with the cytoskeleton and cellular signalling pathways. Because integrins can be activated by proteins binding to their extracellular or their intracellular domains, they can function in a bidirectional fashion by transmitting information outside-in (cues from the extracellular environment) and inside-out (cues from the intracellular environment) of the cell. The integrin family of proteins consists of α subunits and β subunits forming trans- membrane heterodimers. The amino-acid sequence arginine–glycine–aspartic acid, or RGD motif, on target ligands (such as fibronectin, laminin and other extracellular matrix proteins) has binding affinity to the extracellular binding head of integrins. For further reading on integrins and their ligands properties, see Barczyk et al (2010). The actin-binding protein talin binds the cytoplasmic domain of integrin β subunit and activates integrins. Vinculin interacts with talin and α-actinin cross-links two filaments of actin. Kindlins, named after the gene mutated in Kindler’s syndrome, a skin blistering disease, inter - act with talin to activate integrins.extravasation across the endothelium. For additional reading on the significance and mechanism of homing, see Girard et al (2012). Three major types of selectin include L-selectin (for lymphocytes), E-selectin (for endothelial cells) and P-selectin (for platelets). Calcium-independent cell adhesion molecules: Ig-Cams, nectins and integrins Ig-CAMs are cell-surface glycoproteins with an extracellular domain characterized by a variable number of immunoglobulin-like loops. Most Ig-CAMs have a transmembrane domain; others are attached to the cell surface by a glycophosphatidyl inositol (GPI) anchor. As in cadherins, Ig-CAMs establish homophilic interactions contributing to cell–cell adhesion, although in a Ca 2+-independent manner. The cyto- plasmic tail of Ig-CAMs also interacts with cytoskeletal components such as F-actin, ankyrins and spectrin. Ig-CAMs can directly or indirectly bind growth factor receptors and control their internalization. Different types are expressed in different tissues. Neural cell adhe - sion molecules (N-CAMs) are found on a number of cell types but are expressed widely by neural cells. Intercellular adhesion molecules (ICAMs) are expressed on vascular endothelial cells. Cell adhesion molecule binding is predominantly homophilic, although some use a heterophilic mechanism, e.g. vascular intercellular adhesion molecule (VCAM), which can bind to integrins. Nectins and nectin-like molecules (Necls) are members of the Ig-CAM superfamily (see Takai et al (2008) for further reading on nectins and Necls). They have an extracellular domain with three Ig-like Fig . 1 .19 Intercellular junctions: the apical junctional complex and other junctional specializations, illustrating the protein components of each junction and of the basal lamina . An anastomotic network of contacts between adjacent cell membranes forms a tight occluding junction . Basal plasma membrane is attached to a basal lamina at a hemidesmosome . In a gap junction, numerous channels (pores within connexons) are clustered to form a plaque-like junctional region between adjacent plasma membranes . (A and C are transmission electron micrographs; B and D are freeze-fractured preparations .) A, An apical junctional complex . B, A tight junction . C, A hemidesmosome . D, A gap junction . (B, Courtesy of Dr Andrew Kent, King’s College London . D, Courtesy of Professor Dieter Hülser, University of Stuttgart . A,C, From human tissue, courtesy of Dr Bart Wagner, Histopathology Department, Sheffield Teaching Hospitals, UK . Diagram modified from Kierszenbaum AL, Tres LL . 2012 . Histology and Cell Biology: An Introduction to Pathology . 3rd ed, Philadelphia: Elsevier, Saunders; 2011 .) S S S SFibronectin Type IV collagen CollagensClaudin Occludin ZO-1, ZO-2 and ZO-3 Afadin–nectin complex Plakoglobin, plakophilin and desmoplakinAfadin–nectin complex Cadherins Cadherins Integrin Integrin LamininSelectinsIg-CAMs Catenin complex Actin Actin Talin VinculinIntermediate filaments Intermediate filaments Nidogen (entactin) PerlecanTight (occluding) junctionTight (occluding) junction Tight (occluding) junction Zonula adherens Macula adherens HemidesmosomeGap junctionZonula adherens Macula adherensAPICAL DOMAIN BASOLATERAL DOMAIN BASAL LAMINA APICAL JUNCTIONAL COMPLEXA C DB Gap junction Hemidesmosome

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Basic structure and function of cells 24.e1 CHaPTER 1 Homing, a process that also enables thymus-derived T cells (see Ch. 4) to home in on lymph nodes, consists of two phases. In the first, selectin phase, carbohydrate ligands on the surface of leukocytes adhere loosely to selectins present on the surface of endothelial cells. During the second, cooperative sequential integrin phase, strong adhesion permits the transendothelial migration of leukocytes into the extravas - cular space in cooperation with cell adhesion molecules of the Ig-CAM superfamily. Nectins can interact homophilically or heterophilically with other nectins to mediate, primarily, adhesion. The intracellular domain of nectins binds to the cytoplasmic adaptor protein afadin, which links to actin, whereas Necls interact with scaffolding proteins but not to afadin. Necls are involved in a large variety of cellular functions, including axon–glial interaction, Schwann cell differentiation and myelination. In humans there are about 18 α-subunit subtypes and 8 β-subunit subtypes, which produce 24 integrin heterodimers. The subunits are associated by non-covalent interactions and consist of an extracellular ligand-binding head, two multidomain segments, two single-pass trans- membrane segments and two cytoplasmic tails. Upon binding of extra- cellular ligands, integrins undergo a conformational change (integrin activation), which allows the recruitment of several cytoplasmic F-actin activator proteins (such as talin, vinculin, α-actinin and kindlins) to their short cytoplasmic domain. This results in the formation of a protein complex that interacts with the actin cytoskeleton. In addition, the protein complex promotes the recruitment and activation of several protein kinases (such as focal adhesion kinase), leading to the activation of signalling pathways essential for several cellular activities such as cell migration, proliferation, survival and gene expression.

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ageing, cellular senescence, cancer and apoptosis 25 CHaPTER 1 smooth muscle cells, in the intercalated discs of cardiac muscle cells and between glial cells and neurones. The junctions involve cadherins attached indirectly to actin filaments on the inner side of the membrane. Desmosomes (maculae adherentes) Desmosomes are limited, plaque-like areas of particularly strong inter - cellular contact. In epithelial cells, they may be located subjacent to the tight junction and zonula adherens belts, forming collectively the epi - thelial apical junctional complex (see Fig. 1.19A). The intercellular gap is approximately 25 nm; it is filled with electron-dense filamentous material (the intercellular cadherins) running transversely across it and is also marked by a series of densely staining bands (the cytoplasmic dense plaques) running parallel to the cell surfaces. Adhesion is medi - ated by Ca2+-dependent cadherins, desmogleins and desmocollins. Within the cells on either side, each cytoplasmic dense plaque underlies the plasma membrane and consists of the proteins plakophilin, desmo- plakin and plakoglobin ( γ-catenin), into which the ends of intermedi - ate filaments are inserted. The type of intermediate filament depends on the cell type, e.g. keratins are found in epithelia and desmin fila - ments are found in cardiac muscle cells. Desmosomes form strong anchorage points, likened to spot-welds, between cells subject to mechanical stress, e.g. in the prickle cell layer of the epidermis, where they are extremely numerous and large. Hemidesmosomes Hemidesmosomes are asymmetric anchoring junctions found between the basal side of epithelial cells and the associated basal lamina. The latter is a component of the basement membrane and contains laminin, an integrin ligand. The other component of the basement membrane is the reticular lamina, a collagen-containing layer produced by fibroblasts that also contains fibronectin, another integrin ligand. Hemidesmosomes resemble a single-sided desmosome, anchored on one side to the plasma membrane, and on the other to the basal lamina and adjacent collagen fibrils ( Fig. 1.19C). The plaque has distinct pro - teins not seen in the plaques of a zonula adherens or a macula adher - ens: BPAG1 (bullous pemphigoid antigen 1), a member of the plakin family, and BPAG2 (bullous pemphigoid antigen 2), which possesses an extracellular collagenous domain. BPAG1 and BPAG2 were initially detected in patients with bullous pemphigoid, an autoimmune blister- ing disease. On the cytoplasmic side of the dense plaque there is a less dense plate into which keratin filaments are inserted, where they inter - act with the protein plectin associated with integrin α6β4. Hemidesmo- somes use integrins and anchoring filaments (laminin 5) as their adhesion molecules anchored to the basal lamina, whereas desmo - somes use cadherins. Focal adhesion plaques Less highly structured attachments with a similar arrangement exist between many other cell types and their surrounding matrices, e.g. between smooth muscle cells and their matrix fibrils, and between the ends of skeletal muscle cells and tendon fibres. The smaller, punctate adhesions resemble focal adhesion plaques, which are regions of local attachment between cells and the extracellular matrix. They are typically situated at or near the ends of actin filament bundles (stress fibres), anchored through intermediary proteins to the cytoplasmic domains of integrins. In turn, these are attached at their external ends to collagen or other filamentous structures in the extracellular matrix. They are usually short-lived; their formation and subsequent disruption are part of the motile behaviour of migratory cells. See Geiger et al (2009) for further reading on focal adhesions. Gap junctions (communicating junctions) Gap junctions resemble tight junctions in transverse section, but the two apposed lipid bilayers are separated by an apparent gap of 3 nm, which is bridged by a cluster of transmembrane channels (connexons). Each connexon is formed by a ring of six connexin proteins whose external surfaces meet those of the adjacent cell in the middle. A minute central pore links one cell to the next (Fig. 1.19D). Larger assemblies of many thousands of channels are often packed in hexagonal arrays. Gap junctions occur between numerous cells, including hepatocytes and cardiac myocytes. AGEING, CELLULAR SENESCENCE, CANCER AND APOPTOSIS Ageing is a universal feature of biological organisms, defined by a gradual decline over time in cell and tissue function that often, but not Genetic mutations in integrins or integrin regulators have been asso - ciated with Glanzmann’s thrombasthenia (caused by mutations in integrin β3 subunit), the immunodeficiency disorder leukocyte adhe - sion deficiency types I and III (determined by mutations in integrin β2 subunit and kindlin 3, respectively) and skin diseases (caused by muta - tions in kindlin 1 and integrin α2, α6 and β3 subunits). Integrins are essential in the homing process, following the selectin phase, and are also involved in tumour progression and metastasis. Specialized intercellular junctions Specialized cell–cell junctions are the hallmark of all epithelial tissues. There are two major categories: symmetric junctions and asymmetric junctions. Symmetric junctions may be subdivided into three types: tight junctions (also known as occluding junctions or zonulae occlu - dentes); anchoring junctions (including zonulae adherentes, or belt desmosomes, and maculae adherentes, or spot desmosomes); and com - munication junctions, represented by gap junctions. Tight junctions and anchoring junctions are components of the epithelial apical junctional complex. Hemidesmosomes are asymmetric junctions (see Fig. 1.19). Tight junctions (occluding junctions, zonulae occludentes) Tight junctions are the most apical component of the epithelial apical junctional complex. The main functions of tight junctions are the regu - lation of the paracellular permeability of the epithelial layer and the formation of an apical–basolateral intramembrane diffusion barrier, the hallmark of epithelial cell polarity. Tight junctions form a continu - ous belt (zonula) around the cell perimeter, near the apical domain of epithelial cells, and are connected to the actin cytoskeleton. At the site of the tight junction, the plasma membranes of adjacent cells come into close contact, so that the space between them is obliterated. Freeze- fracture electron microscopy shows that the contact between these membranes is represented by branching and anastomosing sealing strands of protein particles on the P (protoplasmic) face of the lipid bilayer (Fig. 1.19A,B). A tight junction contains numerous proteins: occludins and claudins, members of the tetraspanin family of proteins, containing four transmembrane domains, two loops and two cytoplas - mic tails – occludins and tetraspanins provide the molecular basis for the formation of the branching and anastomosing strands seen in freeze-fracture preparations; the afadin–nectin complex and junctional adhesion molecules (JAMs), each forming cis-homodimers and interact - ing with each other through their extracellular domains (forming trans- homodimers) – nectins and JAMs are members of the immunoglobulin superfamily, and the afadin component of the afadin–nectin complex interacts with F-actin; and cytosolic zonula occludens proteins 1, 2 and 3 (ZO-1, ZO-2 and ZO-3). ZO-1 protein is associated with afadin and the intracellular domain of JAMs. All three ZO proteins facilitate the reciprocal interaction of occludins, claudins and JAMs with F-actin. Defects in paracellular magnesium permeability and reabsorption in kidneys occur when there is a mutation in claudin 16 and claudin 19 (renal magnesium wasting). For further reading on claudins, see Escudero-Esparza et al (201 1). For further reading on JAMs, see Bazzoni (2003). anchoring junctions In contrast to tight junctions, zonulae adherentes and maculae adher - entes are characterized by the presence, along the cytosolic sides of the plasma membranes of adjacent epithelial cells, of symmetric dense plaques connected to each other across the intercellular space by cad - herins. They differ in that F-actin is associated with plaques in zonulae adherentes and intermediate filaments are linked to plaques in maculae adherentes. Zonula adherens (belt desmosome) A zonula adherens is a continuous belt-like zone of adhesion parallel and just basal to a tight junction and also encircling the apical perimeter of epithelial cells. Ca2+-dependent cell adhesion molecules (members of the desmoglein and desmocollin families of cadherins) are key com - ponents of a zonula adherens. In addition to the cadherin–catenin complex, a zonula adherens also houses the afadin–nectin complex. A specific component of a zonula adherens is a cytoplasmic dense plaque attached to the cytosolic side of the plasma membrane. It con - sists of desmoplakin, plakophilin and plakoglobin proteins (the latter is also known as γ-catenin). A similar plaque is seen in a macula adhe - rens or spot desmosome (see below). Fascia adherens A fascia adherens is similar to a zonula adherens, but is more limited in extent and forms a strip or patch of adhesion, e.g. between

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Basic structure and function of cells 25.e1 CHaPTER 1 Essentially, two molecules, cadherins and afadin, link to the actin cytoskeleton. In cultured cells, nectins appear to initiate the formation of a zonula adherens before the involvement of cadherins.

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BaSIC STR uCTuRE aNd fu NCTION Of CEllS 26 SECTION 1 enter the cell. The intrinsic mitochondrial route involves the release of cytochrome c from the space between the inner and outer mitochon - drial membranes into the cytosol. Extrinsic and intrinsic pathways work cooperatively in the subsequent activation of a family of initiator- effector proteases, known as caspases (cysteine aspartic acid-specific proteases), which are present in healthy cells as inactive precursor enzymes or zymogens. Activation of caspases 3, 6 and 7 mediates apop - tosis by initiating a cascade of degradative processes that target major constituents of the cell cytoskeleton, producing membrane blebbing, a distinctive feature of apoptosis caused by cytosolic and nuclear frag - ments flowing into the developing apoptotic bodies. Caspase cleavage inactivates many systems that normally promote damage repair and support cell viability, and activates a number of proteins that promote the death and disassembly of the cell. For further reading on apoptosis, see Taylor et al (2008).always, decreases the longevity of an individual. The hallmarks of ageing are reviewed in López-Otín et al (2013). Cellular senescence is defined by an irreversible arrest in cell prolif - eration when cells experience DNA damage at telomeres and a decrease in mitogenic signalling. In contrast to reversibly arrested quiescent cells in G 0 of the cell cycle, senescent growth arrest is irreversible; cells in this state cannot be stimulated to proliferate by known stimuli and cannot be prompted to re-enter the cell cycle by physiological mechanisms. For further reading on senescence and the cell cycle, see Chandler and Peters (2013). Senescent cells can cause or foster degenerative diseases. In old age, cellular senescence in humans determines typical pathologies, in - cluding atherosclerosis leading to stroke, osteoporosis, macular degen - eration, cardiopulmonary and renal failure, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Senescent cells undergo changes in gene expression, which result in the secretion of proinflammatory cytokines, growth factors and pro - teases, activities that collectively define a senescence-associated secre - tory phenotype capable of triggering angiogenesis, inflammatory responses, stem cell renewal and differentiation, and which may also determine resistance to cancer chemotherapy. Senescent cells can be identified histochemically by their expression of either senescence- associated β-galactosidase, a lysosomal marker which is overexpressed in these cells, or the tumour suppressor protein p16 INK4a, which pro- motes the formation of senescence-associated chromatin. For further reading on ageing, cellular senescence and cancer, see Campisi (2013). Cellular senescence can be caused by a disruption of metabolic signalling pathways, derived from mitogens and proliferation factors, and the activation of tumour suppressors, combined with telomere shortening and genomic damage. See Sahin and DePinho (2012) for further reading. Cellular senescence suppresses tumorigenesis because cell prolifera - tion is required for cancer development. However, senescent cells can stimulate the proliferation and malignant progression of adjacent pre - malignant cells by the release of senescence-inducing oncogenic stimuli. Cancer cells must harbour mutations to prevent telomere-dependent and oncogene-induced senescence, such as in the p53 and p16- retinoblastoma protein pathways. See López-Otín et al (2013) for further reading on the pathogenesis of ageing. Apoptosis Cells die as a result of either tissue injury (necrosis) or the internal activation of a ‘suicide’ programme (apoptosis) in response to extrinsic or intrinsic cues. Apoptosis (programmed cell death) is defined by the controlled demolition of cellular constituents and the ultimate uptake of apoptotic cell fragments by other cells to prevent immune responses. Some senescent cells become resistant to cell-death signalling, i.e. they are apoptosis-resistant. In effect, senescence blocks growth of damaged or stressed cells, whereas apoptosis quickly disposes of them. Apoptosis is a central mechanism controlling multicellular development. During morphogenesis, apoptosis mediates activities such as the separation of the developing digits, and plays an important role in regulating the number of neurones in the nervous system (the majority of neurones die during development). Apoptosis also ensures that inappropriate or inefficient T cells are eliminated in the thymus during clonal selection. The morphological changes exhibited by necrotic cells are very dif - ferent from those seen in apoptotic cells. Necrotic cells swell and sub - sequently rupture, and the resulting debris may induce an inflammatory response. Apoptotic cells shrink, their nuclei and chromosomes frag - ment, forming apoptotic bodies, and their plasma membranes undergo conformational changes that act as a signal to local phagocytes. The dead cells are removed rapidly, and as their intracellular contents are not released into the extracellular environment, inflammatory reactions are avoided; the apoptotic fragments also stimulate macrophages to release anti-inflammatory cytokines. Apoptosis and cell proliferation are intimately coupled; several cell cycle regulators can influence both cell division and apoptosis. The signals that trigger apoptosis include withdrawal of survival factors or exposure to inappropriate proliferative stimuli. Three main routes to the induction of apoptosis have been established ( Fig. 1.20). Two, the Fas ligand (FasL) pathway and the granzyme B pathway, are extrinsic, whereas the mitochondrial route is intrinsic. The Fas ligand (FasL) pathway involves binding of FasL to death receptors on the plasma membrane and recruitment of adaptor proteins, such as the Fas-associ - ated death domain proteins, followed by the recruitment and activation of caspase 8. The granzyme B pathway involves creation of a perforin plasma membrane channel enabling the caspase-like granzyme B to Fig . 1 .20 Caspase activation pathways during apoptosis . A, The granzyme B extrinsic pathway activates caspase 8 and caspase 3 following entry of granzyme B across the plasma membrane pore-forming protein, perforin . This pathway is observed in cytotoxic T cells or natural killer cells for delivery of the protease granzyme B to target cells . B, The Fas ligand (FasL) extrinsic pathway is initiated by binding of FasL to clustered transmembrane death receptors that recruit adaptor proteins, such as the Fas-associated death-domain protein (FADD) to their intracellular domain, which in turn recruits and aggregates caspase 8 molecules, which become activated . Activated caspase 8 activates caspase 7 and caspase 3 . C, The cytochrome c intrinsic pathway starts when granzyme B or activated caspase 8 causes the truncation by proteolysis of the protein BIDD (BH3-interacting domain death agonist), which penetrates a mitochondrion through BAX–BAK (BCL-2 associated X protein–BCL-2 antagonist killer) channel proteins on the outer mitochondrial membrane, causing the release of cytochrome c. Cytochrome c enables the assembly of the apoptosome (consisting of seven molecules of apoptosis protease-activating factor-1 (APAF1) and seven molecules of caspase 9), which in turn activates caspase 3 and caspase 7 . Finally, the proteolytic activation cascade of caspase 6, caspase 2, caspase 8 and caspase 10 executes cell deconstruction . Fas ligand Granzyme B Granzyme BPerforinDeath receptors FADD BIDDCaspase 8 Caspase 3Cytochrome c pathway CGranzyme B pathwayA FasL pathwayB Caspase 9ApoptosomeMitochondrion Cytochrome c Caspase 7Active caspase 8 Caspase 3 Caspase 2 Caspase 10Caspase 6 Caspase 8BAX–BAK channels Video 1 .1 Mitosis in a cell with fluorescently-labelled chromosomes and microtubules .  Bonus  e-book  video

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Basic structure and function of cells 26.e1 CHaPTER 1 The ends of the chromosomes, or telomeres, become shorter and more dysfunctional with each DNA replication round. Telomere short - ening has been shown to activate DNA damage responses, leading to mitochondrial dysfunction (a decrease in production of ATP and an increase in reactive oxygen species) and the activation of p53, which induces growth arrest, apoptosis and senescence of stem cells and pro - genitor cells. p53 interconnects with different longevity metabolic sig - nalling pathways, including the insulin, insulin-like growth factor I (IGFI) and mammalian target of rapamycin (mTOR) pathways, which are known to regulate lifespan by increasing the expression of genes involved in stress resistance and energy balance. Mutations in TERC (the RNA component of telomerase) and TERT (the catalytic component of telomerase) are found in patients with the premature ageing syndrome, dyskeratosis congenita (poor growth of fingernails and toenails, skin pigmentation and oral leukoplakia). Other important contributors to cell senescence are dysregulated autophagy and lack of disposal of misfolded proteins by the ubiquitin–26S proteasome machinery. These responses are collectively designated telomere-initiated cellular senescence.

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27 CHaPTER 1Key references KEY REFERENCES Bray D 2001 Cell Movements. New York: Garland. A comprehensive presentation of the structural and molecular features of the cytoskeleton, including its properties and behaviour in cell and organelle movement in living cells. Burke B, Stewart CL 2013 The nuclear lamins: flexibility in function. Nat Rev Mol Cell Biol 14:13–24. An up-to-date, detailed description of the nuclear lamina and its major components, lamins, members of the intermediate filament protein family. Chinnery PF, Hudson G 2013 Mitochondrial genetics. Br Med Bull 106: 135–59. A detailed survey of the involvement of mitochondrial DNA (mtDNA) defects in human disease, with a specific focus on the mechanisms controlling mtDNA inheritance. Girard JP, Moussion C, Förster R 2012 HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat Rev Immunol 12: 762–73.A comprehensive description of the continuous trafficking of immune cells across the vascular endothelium (homing) engaging cell adhesion molecules. Kierszenbaum AL, Tres LL 2012 Histology and Cell Biology: An Introduction to Pathology. Philadelphia: Elsevier, Saunders. An integrated visual view of histology, cell biology and basic pathology focused on structure and function, including human pathological examples from a molecular viewpoint. López-Otín C, Blasco MA, Partridge L et al 2013 The hallmarks of aging. Cell 153:1 194–217.A review of recent advances in the pathogenesis of ageing, defined by a gradual loss of physiological integrity leading to major human pathological conditions. Genomic instability, telomerase attrition, epigenetic alterations, loss of proteolysis and mitochondrial dysfunction are considered. Pollard TD, Earnshaw WC 2008 Cell Biology. Philadelphia: Elsevier, Saunders. A detailed and comprehensive account of structural and molecular aspects of cell biology, including abnormalities related to human disease. Porter RM, Lane EB 2003 Phenotypes, genotypes and their contribution to understanding keratin function. Trends Genet 19:278–85. A correlation of human epithelial pathological conditions with mouse mutant studies focused on keratin diversity required for cells to attune to mechanical and biochemical signalling. Saftig P, Klumperman J 2009 Lysosome biogenesis and lysosomal mem - brane proteins: trafficking meets function. Nat Rev Mol Cell Biol 10: 623–35.The participation of lysosomes in the degradation of extracellular material internalized by endocytosis and lysosomal sorting pathways, reviewed within the context of human diseases resulting from defective lysosomal biogenesis. Scholey JM 2008 Intraflagellar transport motors in cilia: moving along the cell’s antenna. J Cell Biol 180:23–9. Ciliopathies derived from the defective assembly, maintenance and function of the axoneme in motile and sensory cilia, considered within the framework of intraflagellar transport proteins and associated molecular motors.

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Basic structure and function of cells 27.e1 CHaPTER 1 REFERENCES Baldari CT, Rosenbaum J 2010 Intraflagellar transport: it’s not just for cilia anymore. Curr Opin Cell Biol 22:75–80. Barczyk M, Carracedo S, Gullberg D 2010 Integrins. Cell Tissue Res 339:269–80. Bazzoni G 2003 The JAM family of junctional adhesion molecules. Curr Opin Cell Biol 15:525–30. Boisvert FM, van Koningsbruggen S, Navascués J et al 2007 The multifunc- tional nucleolus. Nat Rev Mol Cell Biol 8:574–85. Boya P, Reggiori F, Codogno P 2013 Emerging regulation and functions of autophagy. Nat Cell Biol 15:713–20. Braverman NE, D’Agostino MD, Maclean GE 2013 Peroxisome biogenesis disorders: biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev 17:187–96. Bravo R, Parra V, Gatica D et al 2013 Endoplasmic reticulum and the unfolded protein response: dynamics and metabolic integration. Int Rev Cell Mol Biol 301:215–90. Bray D 2001 Cell Movements. New York: Garland. A comprehensive presentation of the structural and molecular features of the cytoskeleton, including its properties and behaviour in cell and organelle movement in living cells. Brieher WM, Yap AS 2013 Cadherin junctions and their cytoskeleton(s). Curr Opin Cell Biol 25:39–46. Briscoe J, Thérond PP 2013 The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 14:418–31. Brown JW, McKnight CJ 2010 Molecular model of the microvillar cytoskel - eton and organization of the brush border. PLoS One 5:e9406. Burke B, Stewart CL 2013 The nuclear lamins: flexibility in function. Nat Rev Mol Cell Biol 14:13–24.An up-to-date, detailed description of the nuclear lamina and its major components, lamins, members of the intermediate filament protein family. Campisi J 2013 Aging, cellular senescence and cancer. Annu Rev Physiol 75:685–705. Chandler H, Peters G 2013 Stressing the cell cycle in senescence and aging. Curr Op Cell Biol Dec; 25:765–71. Chinnery PF, Hudson G 2013 Mitochondrial genetics. Br Med Bull 106:135–59.A detailed survey of the involvement of mitochondrial DNA (mtDNA) defects in human disease, with a specific focus on the mechanisms controlling mtDNA inheritance. Clarke PR, Zhang C 2008 Spatial and temporal coordination of mitosis by Ran GTPase. Nat Rev Mol Cell Biol 9:464–77. Dominguez R 2010 Structural insights into de novo actin polymerization. Curr Opin Struct Biol 20:217–25. Escudero-Esparza A, Jiang WG, Martin TA 201 1 The Claudin family and its role in cancer and metastasis. Front Biosci 16:1069–83. Geiger B, Spatz JP, Bershadsky AD 2009 Environmental sensing through focal adhesions. Nat Rev Mol Cell Biol 10:21–33. Girard JP, Moussion C, Förster R 2012 HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat Rev Immunol 12:762–73.A comprehensive description of the continuous trafficking of immune cells across the vascular endothelium (homing) engaging cell adhesion molecules. Gönczy P 2012 Towards a molecular architecture of centriole assembly. Nat Rev Mol Cell Biol 13:425–35. Hammer JA 3rd, Sellers JR 2012 Walking to work: roles for class V myosins as cargo transporters. Nat Rev Mol Cell Biol 13:13–26. Hao L, Scholey JM 2009 Intraflagellar transport at a glance. J Cell Sci 122:889–92. Herrmann H, Bär H, Kreplak L et al 2007 Intermediate filaments: from cell architecture to nanomechanics. Nat Rev Mol Cell Biol 8:562–73. Jin H, Nachury MV 2009 The BBSome. Curr Biol 19:R472–3. Kierszenbaum AL, Rivkin E, Tres LL 201 1 Cytoskeletal track selection during cargo transport in spermatids is relevant to male fertility. Spermatogen - esis 1:221–30. Kierszenbaum AL, Tres LL 2012 Histology and Cell Biology: An Introduction to Pathology. Philadelphia: Elsevier, Saunders. An integrated visual view of histology, cell biology and basic pathology focused on structure and function, including human pathological examples from a molecular viewpoint. López-Otín C, Blasco MA, Partridge L et al 2013 The hallmarks of aging. Cell 153:1 194–217.A review of recent advances in the pathogenesis of ageing, defined by a gradual loss of physiological integrity leading to major human pathological conditions. Genomic instability, telomerase attrition, epigenetic alterations, loss of proteolysis and mitochondrial dysfunction are considered. Luger K, Dechassa ML, Tremethick DJ 2012 New insights into nucleosome and chromatin structure: an ordered state or a disordered affair? Nat Rev Mol Cell Biol 13:436–47. Mostowy S, Cossart P 2012 Septins: the fourth component of the cytoskel - eton. Nat Rev Mol Cell Biol 13:183–94. Muller PA, Vousden KH 2013 p53 mutations in cancer. Nat Cell Biol 15:2–8. Munro S 201 1 The golgin coiled-coil proteins of the Golgi apparatus. Cold Spring Harb Perspect Biol 3:a005256. Nandakumar J, Cech TR 2013 Finding the end: recruitment of telomerase to telomeres. Nat Rev Mol Cell Biol 14:69–82. Pan X, Hobbs RP, Coulombe PA 2012 The expanding significance of keratin intermediate filaments in normal and diseased epithelia. Curr Op Cell Biol 25:1–10. Park C, Cuervo AM 2013 Selective autophagy: talking with the UPS. Cell Biochem Biophys 67:3–13. Pollard TD, Earnshaw WC 2008 Cell Biology. Philadelphia: Elsevier, Saunders. A detailed and comprehensive account of structural and molecular aspects of cell biology, including abnormalities related to human disease. Porter RM, Lane EB 2003 Phenotypes, genotypes and their contribution to understanding keratin function. Trends Genet 19:278–85.A correlation of human epithelial pathological conditions with mouse mutant studies focused on keratin diversity required for cells to attune to mechanical and biochemical signalling. Raices M, D’Angelo MA 2012 Nuclear pore complex composition: a new regulator of tissue-specific and developmental functions. Nat Rev Mol Cell Biol 13:687–99. Rotty JD, Wu C, Bear JE 2013 New insights into the regulation and cellular functions of the ARP2/3 complex. Nat Rev Mol Cell Biol 14:7–12. Saftig P, Klumperman J 2009 Lysosome biogenesis and lysosomal mem - brane proteins: trafficking meets function. Nat Rev Mol Cell Biol 10:623–35.The participation of lysosomes in the degradation of extracellular material internalized by endocytosis and lysosomal sorting pathways, reviewed within the context of human diseases resulting from defective lysosomal biogenesis. Sahin E, DePinho RA 2012 Axis of ageing: telomeres, p53 and mitochondria. Nat Rev Mol Cell Biol 13:397–404. Scholey JM 2008 Intraflagellar transport motors in cilia: moving along the cell’s antenna. J Cell Biol 180:23–9.Ciliopathies derived from the defective assembly, maintenance and function of the axoneme in motile and sensory cilia, considered within the framework of intraflagellar transport proteins and associated molecular motors. Settembre C, Fraldi A, Medina DL et al 2013 Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol 14:283–96. Simon DN, Wilson KL 201 1 The nucleoskeleton as a genome-associated dynamic ‘network of networks’ . Nat Rev Mol Cell Biol 12:695–708. Smith CE, Ordovás JM 2012 Update on perilipin polymorphisms and obesity. Nutr Rev 70:61 1–21. Spang A 2013 Traffic COPs: rules of detection. The EMBO J 32:915–16. Takai Y, Miyoshi J, Ikeda W et al 2008 Nectins and nectin-like molecules: roles in contact inhibition of cell movement and proliferation. Nat Rev Mol Cell Biol 9:603–15. Taylor RC, Cullen SP, Martin SJ 2008 Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9:231–41. Theodoulou FL, Bernhardt K, Linka N et al 2013 Peroxisome membrane proteins: multiple trafficking routes and multiple functions? Biochem J 451:345–52. Tomko RJ Jr, Hochstrasser M 2013 Molecular architecture and assembly of the eukaryotic proteasome. Annu Rev Biochem 82:415–45. Tres LL 2005 XY chromosomal bivalent: nucleolar attraction. Mol Reprod Dev 72:1–6. Weinbaum S, Tarbell JM, Damiano ER 2007 The structure and function of the endothelial cell glycocalyx layer. Annu Rev Biomed Eng 9:121–67. Worman HJ 2012 Nuclear lamins and laminopathies. J Pathol 226:316–25.

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28 SECTION 1 CHAPTER 2 Integrating cells into tissues basal lamina, which is synthesized predominantly by the epithelial cells. The basal lamina is described on page 34. Epithelia can usually regenerate when injured. Indeed, many epithe - lia continuously replace their cells to offset cell loss caused by mechani - cal abrasion (reviewed in Blanpain et al (2007)). Blood vessels do not penetrate typical epithelia and so cells receive their nutrition by diffu - sion from capillaries of neighbouring connective tissues. This arrange - ment limits the maximum thickness of living epithelial cell layers. Epithelia, together with their supporting connective tissue, can often be removed surgically as one layer, which is collectively known as a mem - brane. Where the surface of a membrane is moistened by mucous glands it is called a mucous membrane or mucosa, whereas a similar layer of connective tissue covered by mesothelium is called a serous membrane or serosa. CLASSIFICATION Epithelia can be classified as unilaminar (single-layered, simple), in which a single layer of cells rests on a basal lamina; or multilaminar, in which the layer is more than one cell thick. The latter includes: stratified squamous epithelia, in which flattened superficial cells are constantly replaced from the basal layers; urothelium (transitional epi - thelium), which serves special functions in the urinary tract; and other multilaminar epithelia such as those lining the largest ducts of some exocrine glands, which, like urothelium, are replaced only very slowly under normal conditions. Seminiferous epithelium is a specialized multilaminar tissue found only in the testis. Unilaminar (simple) epithelia Unilaminar epithelia are further classified according to the shape of their cells, into squamous, cuboidal, columnar and pseudostratified types. Cell shape may, in some cases, be related to cell volume. Where little cytoplasm is present, there are generally few organelles and there - fore there is low metabolic activity and cells are squamous or low cuboidal. Highly active cells, e.g. secretory epithelia, contain abundant mitochondria and endoplasmic reticulum, and are typically tall cuboi - dal or columnar. Unilaminar epithelia can also be subdivided into those that have special functions, such as those with cilia, numerous microvilli, secretory vacuoles (in mucous and serous glandular cells) or sensory features. Myoepithelial cells, which are contractile, are found as isolated cells associated with glandular structures, e.g. salivary and mammary glands. Squamous epithelium Simple squamous epithelium is composed of flattened, tightly apposed, polygonal cells (squames). This type of epithelium is described as tes - sellated when the cells have complex, interlocking borders rather than straight boundaries. The cytoplasm may in places be only 0.1 µm thick and the nucleus usually bulges into the overlying space (Fig. 2.2A). These cells line the alveoli of the lungs, where their surface area is huge and cytoplasmic volume correspondingly large, and they also form the outer capsular wall of renal corpuscles, the thin segments of the renal tubules and various parts of the inner ear. Because it is so thin, simple squamous epithelium allows rapid diffusion of gases and water across its surface; it may also engage in active transport, as indicated by the presence of numerous endocytic vesicles in these cells. Tight junctions (occluding junctions, zonulae adherentes) between adjacent cells ensure that materials pass primarily through cells, rather than between them. Cuboidal and columnar epithelia Cuboidal and columnar epithelia consist of regular rows of cylindrical cells (Figs 2.2B, C). Cuboidal cells are approximately square in vertical section, whereas columnar cells are taller than their diameter, and both Cells evolved as single, free-living organisms, but natural selection favoured more complex communities of cells, multicellular organisms, where groups of cells specialize during development to carry out specific functions for the body as a whole. This allowed the emergence of larger organisms with greater control over their internal environment and the evolution of highly specialized organic structures such as the brain. The human body contains more than 200 different cell types, sharing the same genome but with different patterns of gene expression. Some cells in the body are essentially migratory, but most exist as cellular aggregates in which individual cells carry out similar or closely related functions in a coordinated manner. These aggregates are termed tissues, and can be classified into a fairly small number of broad catego - ries on the basis of their structure, function and molecular properties. On the basis of their structure, most tissues are divided into four major types: epithelia, connective or supporting tissue, muscle and nervous tissue. Epithelia are continuous layers of cells with little intercellular space, which cover or line surfaces, or have been so derived. In connec- tive tissues, the cells are embedded in an extracellular matrix, which, typically, forms a substantial and important component of the tissue. Muscle consists largely of specialized contractile cells. Nervous tissue consists of cells specialized for conducting and transmitting electrical and chemical signals and the cells that support this activity. There is molecular evidence that this structure-based scheme of clas - sification has validity. Thus the intermediate filament proteins charac - teristic of all epithelia are keratins (Pan et al 2012); those of connective tissue are vimentins; those of muscle are desmins; and those of nervous tissue are neurofilament and glial fibrillary acidic proteins. However, cells such as myofibroblasts, neuroepithelial sensory receptors and ependymal cells of the central nervous system have features of more than one tissue type. Despite its anomalies, the scheme is useful for descriptive purposes; it is widely used and will be adopted here. In this chapter, two of the major tissue categories, epithelia and general connective and supporting tissues, will be described. Special - ized skeletal connective tissues, i.e. cartilage and bone, together with skeletal muscle, are described in detail in Chapter 5 as part of the mus - culoskeletal system overview. Smooth muscle and cardiac muscle are described in Chapter 6. Nervous system tissues are described in Chapter 3. Specialized defensive cells, which also form a migrant population within the general connective tissues, are considered in more detail in Chapter 4, with blood, lymphoid tissues and haemopoiesis. EPITHELIA The term epithelium is applied to the layer or layers of cells that cover the body surfaces or line the body cavities that open on to it. The fate of embryonic epithelial populations is illustrated in Figure 12.3. Epi - thelia function generally as selective barriers that facilitate, or inhibit, the passage of substances across the surfaces they cover. In addition, they may: protect underlying tissues against dehydration, chemical or mechanical damage; synthesize and secrete products into the spaces that they line; and function as sensory surfaces. In this respect, many features of nervous tissue can be regarded as those of a modified epithelium and the two tissue types share an origin in embryonic ectoderm. Epithelia (Fig. 2.1) are predominantly cellular and the little extracel - lular material they possess is limited to the basal lamina. Intercellular junctions, which are usually numerous, maintain the mechanical cohe - siveness of the epithelial sheet and contribute to its barrier functions. A series of three intercellular junctions forms a typical epithelial junc - tional complex: in sequence from the apical surface, this consists of a tight junctional zone, an adherent (intermediate) junctional zone and a region of discrete desmosome junctions. Epithelial cell shape is most usually polygonal and partly determined by cytoplasmic features such as secretory granules. The basal surface of an epithelium lies in contact with a thin layer of filamentous protein and proteoglycan termed the

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Epithelia 29 CHAPTER 2 Sensory epithelia Sensory epithelia are found in special sense organs of the olfactory, gustatory and vestibulocochlear receptor systems. All of these contain sensory cells surrounded by supportive non-receptor cells. Olfactory receptors are modified neurones and their axons pass directly to the brain, but the other types are specialized epithelial cells that synapse with terminals of afferent (and sometimes efferent) nerve fibres. Myoepithelial cells Myoepithelial cells, which are also sometimes termed basket cells, are fusiform or stellate in shape ( Fig. 2.3), contain actin and myosin fila - ments, and contract when stimulated by nervous or endocrine signals. They surround the secretory portions and ducts of some glands, e.g. mammary, lacrimal, salivary and sweat glands, and lie between the basal lamina and the glandular or ductal epithelium. Their contraction assists the initial flow of secretion into larger conduits. Myoepithelial cells are ultrastructurally similar to smooth muscle cells in the arrange - ment of their actin and myosin, but differ from them because they originate, like the glandular cells, from embryonic ectoderm or endo - derm. They can be identified immunohistochemically on the basis of the co-localization of myofilament proteins (which signify their con - tractile function ( Fig. 2.4)) and keratin intermediate filaments (which accords with their epithelial lineage). Multilaminar (stratified) epithelia Multilaminar epithelia are found at surfaces subjected to mechanical damage or other potentially harmful conditions. They can be divided into those that continue to replace their surface cells from deeper layers, designated stratified squamous epithelia, and others in which replace - ment is extremely slow except after injury. Stratified squamous epithelia Stratified squamous epithelia are multilayered tissues in which the formation, maturation and loss of cells is continuous, although the rates of these processes can change, e.g. after injury. New cells are formed in the most basal layers by the mitotic division of stem cells and transit (or transient) amplifying cells. The daughter cells move more superficially, changing gradually from a cuboidal shape to a more are polygonal when sectioned horizontally. Commonly, microvilli are found on their free surfaces, which considerably increases the absorp - tive area, e.g. in the epithelia of the small intestine (columnar cells with a striated border of very regular microvilli), the gallbladder (columnar cells with a brush border of microvilli); proximal convoluted tubules of the kidney (large cuboidal to low columnar cells with brush borders); and the epididymis (columnar cells with extremely long microvilli, erroneously termed stereocilia). Ciliated columnar epithelium lines most of the respiratory tract, except for the lower pharynx and vocal folds, and it is pseudostratified (Fig. 2.2D) as far as the larger bronchioles; it also lines some of the tympanic cavity and auditory tube; the uterine tube; and the efferent ductules of the testis. Submucosal mucous glands and mucosal goblet cells secrete mucus on to the luminal surface of much of the respira - tory tract, and cilia sweep a layer of mucus, trapped dust particles and so on from the lung towards the pharynx in the mucociliary rejection current, which clears the respiratory passages of inhaled particles. Cilia in the uterine tube assist the passage of oocytes and fertilized ova to the uterus. Some columnar cells are specialized for secretion, and aggregates of such cells may be described as glandular tissue. Their apical domains typically contain mucus- or protein-filled (zymogen) vesicles, e.g. mucin-secreting and chief cells of the gastric epithelium. Where mucous cells lie among non-secretory cells, e.g. in the intestinal epithelium, their apical cytoplasm and its secretory contents often expand to produce a characteristic cell shape, and they are known as goblet cells (see Fig. 2.2D). For further details of glandular tissue, see page 32, and for the characteristics of mucus, see page 40. Pseudostratified epithelium Pseudostratified epithelium is a single-layered (simple) columnar epi - thelium in which nuclei lie at different levels in a vertical section (Fig. 2.2D). All cells are in contact with the basal lamina throughout their lifespan, but not all cells extend through the entire thickness of the epithelium. Some constitute an immature basal cell layer of smaller cells, which are often mitotic and able to replace damaged mature cells. Migrating lymphocytes and mast cells within columnar epithelia may also give a similar, pseudostratified appearance because their nuclei are found at different depths. Much of the ciliated lining of the respiratory tract is of the pseudostratified type, and so is the sensory epithelium of the olfactory area.Fig. 2.1 Classification of epithelial tissues and cells. Squamous Cuboidal ColumnarSee also: Mesothelium – lining body cavities Endothelium – lining blood and lymphatic vessels Without surface specializationSecretory With microvilli (brush/striated border)PseudostratifiedCiliatedStratified squamous Stratified cuboidal/columnar Urothelial (transitional)Non-keratinizing Relaxed StretchedKeratinizing COMPLEX DERIVED STRUCTURES • Multicellular – exocrine and endocrine glands• Sensory structures – e.g. taste buds • Tooth germUNILAMINAR (SIMPLE) MULTILAMINAR Specializations • Nervous tissue – often classified separately , but retains many characteristics of its epithelial origins • Seminiferous epithelium

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INTE gRATIN g CEllS INTO TISS uES 30 SECTION 1 Fig. 2.2 A, Simple squamous epithelium lining the outer parietal layer (arrows) of a Bowman’s capsule in the renal corpuscle (RC), stained with the trichrome, Martius Scarlet Blue (MSB). Oval epithelial nuclei project into the urinary space (U), within a highly attenuated cytoplasm. B, Simple cuboidal epithelium lining a group of collecting ducts sectioned longitudinally in the renal medulla. The basement membranes are stained magenta with periodic– acid Schiff (PAS) reagent. C, Simple columnar epithelium covering the tip (off field, right) of a villus in the ileum. Tall, columnar absorptive cells with oval, vertically orientated nuclei bear a striated border of microvilli, just visible as a deeper-stained apical fringe. Numerous interspersed goblet cells are present, with pale apical cytoplasm filled with mucinogen secretory granules and dark, flattened, basally situated nuclei. D, Ciliated columnar pseudostratified epithelium in the respiratory tract, and interspersed goblet cells, with pale, mucinogen granule-filled apical cytoplasm. All human tissues. (All human tissues, courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.) AUU RC B C D Fig. 2.3 Stellate myoepithelial cells (M) wrapped around secretory acini in the lactating mouse mammary gland, seen in the scanning electron microscope after enzymatic depletion of extracellular matrix. Blood capillaries (C) and fibroblasts (F) are also indicated. (Courtesy of Prof. Toshikazu Nagato, Fukuoka Dental College, Japan.) CCF MF MM CCF MF MM Fig. 2.4 Myoepithelial cells (stained brown), in a human breast duct, demonstrated immunohistochemically using antibody to smooth muscle actin. (Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.)

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Epithelia 31 CHAPTER 2 general shape as are seen in the keratinized type, but they do not fill completely with keratin or secrete glycolipid, and they retain their nuclei until they desquamate at the surface. In sites where considerable abrasion occurs, e.g. parts of the buccal cavity, the epithelium is thicker and its most superficial cells may partly keratinize, so that it is referred to as parakeratinized, in contrast to the orthokeratinized state of fully keratinized epithelium. Diets deficient in vitamin A may induce kerati - nization of such epithelia, and excessive doses may lead to its transfor - mation into mucus-secreting epithelium. Stratified cuboidal and columnar epithelia Two or more layers of cuboidal or low columnar cells ( Fig. 2.5C) are typical of the walls of the larger ducts of some exocrine glands, e.g. the pancreas, salivary glands and the ducts of sweat glands, and they pre - sumably provide more strength than a single layer. Parts of the male urethra are also lined by stratified columnar epithelium. The layers are not continually replaced by basal mitoses and there is no progression of form from base to surface, but they can repair themselves if damaged. Urothelium (urinary or transitional epithelium) Urothelium (Fig. 2.5D) is a specialized epithelium that lines much of the urinary tract and prevents its rather toxic contents from damaging surrounding structures. It extends from the ends of the collecting ducts of the kidneys, through the ureters and bladder, to the proximal portion of the urethra. In males it lines the urethra as far as the ejaculatory ducts, then becomes intermittent and is finally replaced by stratified columnar epithelium in the membranous urethra. In females it extends as far as the urogenital membrane. The epithelium appears to be 4–6 cells thick and lines organs that undergo considerable distension and contraction. It can therefore stretch greatly without losing its integrity. In stretching, the cells become flattened form, and are eventually shed from the surface as a highly flattened squame. Typically, the cells are held together by numerous desmosomes to form strong, contiguous cellular sheets that provide protection to the underlying tissues against mechanical, microbial and chemical damage. Stratified squamous epithelia may be broadly subdi - vided into keratinized and non-keratinized types. Keratinized epithelium Keratinized epithelium ( Fig. 2.5A) is found at surfaces that are subject to drying or mechanical stresses, or are exposed to high levels of abra - sion. These include the entire epidermis and the mucocutaneous junc - tions of the lips, nostrils, distal anal canal, outer surface of the tympanic membrane and parts of the oral lining (gingivae, hard palate and fili - form papillae on the anterior part of the dorsal surface of the tongue). Their cells, keratinocytes, are described in more detail on page 141. A distinguishing feature of keratinized epithelia is that cells of the super-ficial layer, the stratum corneum, are anucleate, dead, flattened squames that eventually flake off from the surface. In addition, the tough keratin intermediate filaments become firmly embedded in a matrix protein. This unusual combination of strongly coherent layers of living cells and more superficial strata made of plates of inert, mechanically robust protein complexes, interleaved with water-resistant lipid, makes this type of epithelium an efficient barrier against different types of injury, microbial invasion and water loss. Non-keratinized epithelium Non-keratinized epithelium is present at surfaces that are subject to abrasion but protected from drying ( Fig. 2.5B). These include: the buccal cavity (except for the areas noted above); oropharynx and laryn - gopharynx; oesophagus; part of the anal canal; vagina; distal uterine cervix; distal urethra; cornea; inner surfaces of the eyelids; and the vestibule of the nasal cavities. Cells go through the same transitions in Fig. 2.5 A, Keratinized stratified squamous epithelium in thin skin. Pigmented melanocytes are seen in the basal layer and a few keratinocytes of the prickle cell layer also contain melanin granules. The dead, keratinized layer (K) lacks nuclei. B, Non-keratinized stratified squamous epithelium of the uterine ectocervix, stained with periodic–acid Schiff (PAS) reagent. The basement membrane (short arrows) and superficial squames, which retain their nuclei, are PAS-positive; squames sloughing off the surface are indicated (long arrow). C, Stratified low columnar epithelium of an interlobular excretory duct of the sublingual salivary gland. D, Urothelium (transitional epithelium) lining the relaxed urinary bladder. The most superficial cells have a thickened plasma membrane as a result of the presence of intramembranous plaques, which give an eosinophilic appearance to the luminal surface (arrows). All human tissues. (All human tissues, courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.) K A B C D

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INTE gRATIN g CEllS INTO TISS uES 32 SECTION 1 secrete small amounts of protein by a merocrine mechanism, and have been reclassified as merocrine glands. In apocrine glands, some of the apical cytoplasm is pinched off with the contained secretions, which are stored in the cell as membrane-free droplets (see Fig. 2.6). The best-understood example of this is the secre - tion of milk fat by mammary gland cells, in which a small amount of cytoplasm is incorporated into the plasma membrane-bound lipid globule as it is released from the cell. Larger amounts of cytoplasm are included in secretions by specialized apocrine sweat glands in the axilla (Stoeckelhuber et al 201 1) and anogenital regions of the body. In some tissues there is a combination of different types of secretion, e.g. mammary gland cells secrete milk fat by apocrine secretion and milk protein, casein, by merocrine secretion. In holocrine glands (see Fig. 2.6), e.g. sebaceous glands in the skin, the cells first fill with secretory products (lipid droplets or sebum, in this instance), after which the entire cell disintegrates to liberate the accumulated mass of secretion into the adjacent duct or, more usually, hair follicle. Structural and functional classification Exocrine glands are either unicellular or multicellular. The latter may be in the form of simple sheets of secretory cells, e.g. the lining of the stomach, or may be structurally more complex and invaginated to a variable degree. Such glands (see Fig. 2.6) may be simple units or their connection to the surface may be branched. Simple unbranched tubular glands exist in the walls of many of the hollow viscera, e.g. the small intestine and uterus, whereas some simple glands have expanded, flask- like ends (acini or alveoli). Such glands may consist entirely of secretory cells, or may have a blind-ending secretory portion that leads through a non-secretory duct to the surface, in which case the ducts may modify the secretions as they pass along them. Glands with ducts may be branched (compound) and sometimes form elaborate ductal trees. Such glands generally have acinar or alveo - lar secretory lobules, as in the exocrine pancreas, but the secretory units may alternatively be tubular or mixed tubulo-acinar. More than one type of secretory cell may occur within a particular secretory unit, or individual units may be specialized to just one type of secretion (e.g. serous acini of salivary glands). Exocrine glands are also classified by their secretory products. Secre - tory cells in mucus-secreting or mucous glands have frothy cytoplasm and basal, flattened nuclei. They stain deeply with metachromatic stains and periodic acid–Schiff (PAS) methods that detect carbohydrate resi - dues. However, in general (i.e. non-specific) histological preparations, they are weakly stained because much of their content of water-rich mucin has been extracted by the processing procedures. Secretory cells in serous glands have centrally placed nuclei and eosinophilic secretory storage granules in their cytoplasm. They secrete mainly glycoproteins (including lysozyme) and digestive enzymes. Some glands are almost entirely mucous (e.g. the sublingual salivary gland), whereas others are mainly serous (e.g. the parotid salivary gland). The submandibular gland is mixed, in that some lobules are predominantly mucous and others serous. Mucous acini may share a lumen with clusters of serous cells (seen in routine preparations as serous demilunes). Although this simple approach to classification is useful for general descriptive purposes, the diversity of molecules syn - thesized and secreted by glands is such that complex mixtures often exist within the same cell. ENDOCRINE GLANDS Endocrine glands secrete directly into connective tissue interstitial fluid and thence the circulation. Their cells are grouped around beds of capil- laries or sinusoids, which typically are lined by fenestrated endothelia to allow the rapid passage of macromolecules through their walls. Endocrine cells may be arranged in clusters within vascular networks, in cords between parallel vascular channels or as hollow structures (fol- licles) surrounding their stored secretions. In addition to the cells of specialized ductless endocrine glands (e.g. pituitary, pineal, thyroid and parathyroid), hormone-producing cells also form components of other organ systems. These include: the cells of the pancreatic islets; thymic epithelial cells; renin-secreting cells of the kidney juxtaglomerular appa - ratus; erythropoietin-secreting cells of the kidney; circumventricular organs; interstitial testicular (Leydig) cells; interstitial follicular and luteal ovarian cells; and placental cells (in pregnancy). Some cardiac myocytes, particularly in the walls of the atria, also have endocrine functions. These cells are all described in detail within the appropriate regional sections.flattened without altering their positions relative to each other, because they are firmly connected by numerous desmosomes. However, the urothelium appears to be reduced to only 2–3 cells thick. The epithe - lium is called transitional because of the apparent transition from a stratified cuboidal epithelium to a stratified squamous epithelium, which occurs as it is stretched to accommodate urine, particularly in the bladder. The basal cells are basophilic and contain many ribosomes; they are uninucleate (diploid), and cuboidal when relaxed. More api - cally, they form large binucleate or, more often, polyploid uninucleate cells. The surface cells are the largest and may even be octoploid; in the relaxed state they typically bulge into the lumen as dome-shaped cells with a thickened, eosinophilic glycocalyx or cell coat. Their luminal surfaces are covered by a specialized plasma membrane in which plaques of intramembranous glycoprotein particles are embedded to stiffen the membrane. When the epithelium is relaxed, the surface area of the cells is reduced and the plaques are partially internalized by the hinge-like action of the more flexible interplaque membrane regions. The plaques re-emerge on to the surface when it is stretched. Normally, cell turnover is very slow; cell division is infrequent and is restricted to the basal layer. However, when damaged, the epithelium regenerates quite rapidly. Seminiferous epithelium Seminiferous epithelium is a highly specialized, complex stratified epi-thelium. It consists of a heterogeneous population of cells that form the lineage of the spermatozoa (spermatogonia, spermatocytes, sper- matids), together with supporting cells (Sertoli cells). It is described in detail on page 1275. GLANDS One of the features of many epithelia is their ability to alter the environ - ment facing their free surfaces by the directed transport of ions, water or macromolecules. This is particularly well demonstrated in glandular tissue, in which the metabolism and structural organization of the cells are specialized for the synthesis and secretion of macromolecules, usually from the apical surface. Such cells may exist in isolation amongst other non-secretory cells of an epithelium, e.g. goblet cells in the absorptive lining of the small intestine, or may form highly coherent sheets of epithelium with a common secretory function, e.g. the mucous lining of the stomach and, in a highly invaginated structure, the complex salivary glands. Glands may be subdivided into exocrine glands and endocrine glands. Exocrine glands secrete, usually via a duct, on to surfaces that are continuous with the exterior of the body, including the alimentary tract, respiratory system, urinary and genital ducts and their derivatives, and the skin. Endocrine glands are ductless and secrete hormones directly into interstitial fluid and thence the circulatory system, which conveys them throughout the body to affect the activities of other cells. In addition to strictly epithelial glands, some tissues derived from the nervous system, including the suprarenal medulla and neurohypophy - sis, are neurosecretory. Paracrine glandular cells are similar to endocrine cells but their secretions diffuse locally to cellular targets in the immediate vicinity; many are classed as neuroendocrine cells because they secrete mole- cules used elsewhere in the nervous system as neurotransmitters or neuromodulators. Modes of signalling by secretory cells are illustrated in Figure 1.6. EXOCRINE GLANDS Types of secretory process The mechanism of secretion varies considerably. If the secretions are initially packaged into membrane-bound vesicles, these are conveyed to the cell surface, where they are discharged. In merocrine secretion, which is by far the most common secretory mechanism, vesicle mem - branes fuse with the plasma membrane to release their contents to the exterior (Fig. 2.6). Specialized transmembrane molecules in the secre - tory vesicle wall recognize marker proteins on the cytoplasmic side of the plasma membrane and bind to them. This initiates interactions with other proteins that cause the fusion of the two membranes and the consequent release of the vesicle contents. The stimulus for secretion varies with the type of cell but often appears to involve a rise in intracel - lular calcium. Glands such as the simple sweat glands of the skin, where ions and water are actively transported from plasma as an exudate, were once classified as eccrine glands. They are now known to synthesize and

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glands 33 CHAPTER 2 Isolated endocrine cells also exist scattered amongst other tissues as part of the dispersed (diffuse) neuroendocrine system, e.g. throughout the alimentary and respiratory tracts. Neuroendocrine cells are generally situated within a mucosal epithelium and their bases often rest on the basal lamina (see below). In response to an external stimulus, they secrete their product basally into interstitial fluid. A typical neuroendo - crine cell is shown in Figure 2.7. The secretory granules vary in shape, size and ultrastructure according to cell type. Cells often take the name of the secretion they produce, e.g. gastrin-secreting G cells of the small intestine. Neuroendocrine cells share many of their secretory products with chemical mediators in the nervous system. CONTROL OF GLANDULAR SECRETION The activities of cells in the various tissue and organ systems of the body are tightly regulated by the coordinated activity of the endocrine and autonomic nervous systems. Endocrine (and paracrine) signals reach target cells in interstitial fluid, often via blood plasma, and together with autonomic nervous signals they ensure that the body responds to normal physiological stimuli and adjusts to changes in the external environment. Hormone secretion is itself controlled in a number of ways, e.g. by neural control, regulatory feedback loops or according to various cyclical, rhythmical or pulsatile patterns of release. Endocrine Fig. 2.6 Classification of the different types of epithelial gland. Mechanisms of secretion Structural classification of glands – Simple glands with unbranched ducts Structural classification of glands – Ductal branching pattern of complex glandsA. Merocrine B. Apocrine C. Holocrine A. Unicellular B. Multicellular sheet A. Simple tubular without duct B. Simple tubular with duct C. Simple branched tubular E. Simple acinar or alveolar D. Simple coiled tubular B. Branched acinar/alveolar C. Branched tubulo-acinar A. Branched tubularArrangement of cells glands have a rich vascular supply and their blood flow is controlled by autonomic vasomotor nerves, which can thus modify glandular activity. Glandular activity may also be controlled directly by autonomic secretomotor fibres, which may either form synapses on the bases of gland cells (e.g. in the suprarenal medulla) or release neuromediators in the vicinity of the glands and reach them by diffusion. Alternatively, the autonomic nervous system may act indirectly on gland cells, e.g. on neuroendocrine G cells via histamine, released neurogenically from another neuroendocrine cell in the gastric lining. Such paracrine activities of neuroendocrine cells are also important in the respiratory system. Circulating hormones from the adenohypophysis stimulate syn - thesis and secretion by target cells in many endocrine glands. Such signals, mostly detected by receptors at the cell surface and mediated by second messenger systems, may increase the synthetic activity of gland cells, and may cause them to discharge their secretions by exocy - tosis. Secretions from certain exocrine glandular cells are expressed rapidly from those glands by the contraction of associated myoepithe - lial cells (see Figs 2.3, 2.4) that enclose the secretory units and smaller ducts. Myoepithelial cells may be under direct neural control, as in the salivary glands, or they may respond to circulating hormones, as in the mammary gland, where they respond to the concentration of circulat - ing oxytocin.

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INTE gRATIN g CEllS INTO TISS uES 34 SECTION 1 plasma membrane proteins, e.g. keratinocyte hemidesmosomes are anchored into the lamina densa in the basal lamina of the epidermis. The basal lamina is a delicate felt-like network composed largely of two glycoprotein polymers, laminin and type IV collagen, which self- assemble into two-dimensional sheets interwoven with each other. Early embryonic basal lamina is formed only of the laminin polymer. Two other molecules cross-link and stabilize the network: entactin (nidogen) and perlecan (a large heparan sulphate proteoglycan). Although all basal laminae have a similar form, their thickness and precise molecular composition vary between tissues and even within a tissue, e.g. between the crypts and villi of the small intestine. The iso - forms of laminin and collagen type IV differ in various tissues; thus Schwann cells and muscle cells express laminin-2 (merosin) rather than the prototypical laminin-1. Laminin-5, although not itself a basal lamina component, is found in the hemidesmosomes of the basal epidermis and links the basal lamina with epidermal transmembrane proteins, α 6β4 integrin and collagen type XVII (BPAG2, bullous pem - phigoid antigen 2, one of the targets of the autoimmune blistering skin disease, bullous pemphigoid). The particular isoform of collagen type IV in the basal lamina of different tissues is reflected in tissue-specific disease patterns. Mutations in a collagen expressed by muscle and kidney glomeruli cause Alport’s syndrome, a form of renal failure. Renal failure also occurs in Goodpasture’s syndrome, in which renal basal lamina collagen is targeted by autoantibodies. In Descemet’s membrane in the cornea, collagen type VIII replaces collagen type IV in the much thickened (increasing with age, up to 10 µm,) endothelial basal lamina. The basal lamina of the neuromus - cular junction contains agrin, a heparan sulphate proteoglycan, which plays a part in the clustering of muscle acetylcholine receptors in the plasma membrane at these junctions. RETICULAR LAMINA The reticular lamina consists of a dense extracellular matrix that con - tains collagen. In skin, it contains fibrils of type VII collagen (anchoring fibrils), which bind the lamina densa to the adjacent connective tissue. The high concentration of proteoglycans in the reticular lamina is responsible for the positive reaction of the entire basement membrane to stains for carbohydrates, which is seen in sections prepared for light microscopy. FUNCTIONS OF BASAL LAMINA Basal laminae perform a number of important roles (Iozzo 2005). They form selectively permeable barriers (anionic filters) between adjacent tissues, e.g. in the glomerular filter of the kidney; anchor epithelial and Feedback loops and endocrine axes The pituitary gland, in particular the adenohypophysis, is often termed the master gland because of its central role in endocrine physiological processes. It provides the means by which the central nervous system regulates and integrates, by non-neural mechanisms, the widespread functions of the body, including the activities of other endocrine glands and, often indirectly, exocrine glands such as the breast. Regulatory hormones from the adenohypophysis stimulate synthesis and secretion in target cells of many endocrine glands; these glands therefore respond to, as well as generate, hormonal signals. The hypothalamus and the adenohypophysis in the brain are central to most regulatory feedback loops within the endocrine system. Loops can be either positive or negative, e.g. the hypothalamus stimulates release of follicle stimulating hormone (FSH) by the adenohypophysis, which in turn stimulates ovarian follicular maturation and secretion of oestradiol, which acts on breast and endometrial target tissues. Oestra - diol, in this case, also acts back on the adenohypophysis and hypotha - lamus to reinforce their function positively in a feedback loop. In contrast, hypothalamic and adenohypophysial stimulation of testicular production of testosterone, which acts on targets such as skeletal muscle, is negatively regulated in a feedback loop generated by circulat - ing testosterone. Such negative feedback regulation is a widely utilized physiological mechanism. BASEMENT MEMBRANE AND BASAL LAMINA There is a narrow layer of extracellular matrix, which stains strongly for carbohydrates, at the interface between connective and other tissues, e.g. between epithelia and their supporting connective tissues. In early histological texts this layer was termed the basement membrane. As almost all of its components are synthesized by the epithelium or other tissues, rather than the adjacent connective tissue, it will be dis- cussed here. Electron microscopy revealed that the basement membrane is com - posed of two distinct components. A thin, finely fibrillar layer, the basal lamina, is associated closely with the basal cell surface ( Fig. 2.8). A variable reticular lamina of larger fibrils and glycosaminoglycans of the extracellular matrix underlies this layer and is continuous with the con - nective tissue proper, although it is much reduced or largely absent in some tissues, e.g. surrounding muscle fibres, Schwann cells and capil- lary endothelia. In other tissues, the basal lamina separates two layers of cells and there are no intervening typical connective tissue elements. This occurs in the thick basal lamina of the renal glomerular filter and the basal lamina of the thin portions of the lung interalveolar septa across which gases exchange between blood and air. The basal lamina is usually about 80 nm thick, varying between 40 and 120 nm, and consists of a sheet-like fibrillar layer, the lamina densa (20–50 nm wide), separated from the plasma membrane of the cell it supports by a narrow electron-lucent zone, the lamina lucida. The lamina lucida is absent from tissues prepared by rapid freezing and so may be an artefact. In many tissues this zone is crossed by integral Fig. 2.8 The basal lamina as seen in an electron micrograph, underlying the basal epithelial layer of human skin (see Fig. 7.3). The finely fibrillar dense layer (long arrows) corresponds to the lamina densa, and fine collagen fibrils (*) lie in the subjacent connective tissue. These contribute to the appearance of the basement membrane in light microscope preparations stained for carbohydrate-rich structures. The two cells seen in the upper field are basal keratinocytes (K), joined by desmosomes (short arrow), with dense keratin filaments in their cytoplasm. (Courtesy of J McMillan MD, St John’s Institute of Dermatology, St Thomas’ Hospital, London.) K KFig. 2.7 An electron micrograph of a neuroendocrine cell between two absorptive cells in the colon (rat tissue). Dense neurosecretory granules are seen in the basal cytoplasm, apposed to the basal lamina (arrows). (Courtesy of Michael Crowder MD.)

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Connective and supporting tissues 35 CHAPTER 2 to demand. Embryologically, fibroblasts and adipocytes arise from mes- enchymal stem cells, some of which may remain in the tissues to provide a source of replacement cells postnatally. As noted above, the cells of haemopoietic origin migrate into the tissue from bone marrow and lymphoid tissue. Resident cells Fibroblasts Fibroblasts are usually the most numerous resident cells. They are flat - tened and irregular in outline, with extended processes, and in profile they appear fusiform or spindle-shaped (Fig. 2.10; see also Fig. 2.12). Fibroblasts synthesize most of the extracellular matrix of connective tissue (see Fig. 2.10); accordingly, they have all the features typical of cells active in the synthesis and secretion of proteins. Their nuclei are relatively large and euchromatic, and possess prominent nucleoli. In young, highly active cells, the cytoplasm is abundant and basophilic (reflecting the high concentration of rough endoplasmic reticulum), mitochondria are abundant and several sets of Golgi apparatus are present. In old and relatively inactive fibroblasts (often termed fibro - cytes), the cytoplasmic volume is reduced, the endoplasmic reticulum is sparse and the nucleus is flattened and heterochromatic. Fibroblasts are usually adherent to the fibres of the matrix (collagen and elastin), which they lay down. In some highly cellular structures, e.g. liver, kidney and spleen, and in most lymphoid tissue, fibroblasts and delicate collagenous fibres (type III collagen; reticular fibres) form fibrocellular networks, which are often called reticular tissue. The fibroblasts may then be termed reticular cells or reticulocytes. Fibroblasts are particularly active during wound repair following traumatic injury or inflammation, when tissue mass is lost through cell death. They proliferate and lay down a fibrous matrix that becomes invaded by numerous blood vessels (granulation tissue). Contraction of wounds is, at least in part, caused by the shortening of myofibrob - lasts, specialized contractile fibroblast-like cells (Hinz et al 2012) with properties similar to smooth muscle cells. It was thought that myofi - broblasts differentiated from fibroblasts (reviewed in McAnulty (2007)) or their progenitor mesenchymal stem cells (see below) in granulation tissue. However, recent evidence suggests that in wound healing and in many fibrotic disease processes, including hepatic cirrhosis, the myofi - broblast precursor is the vascular pericyte or a closely related cell (reviewed in Duffield (2012)). In cases where the specialized cells of the damaged region cannot divide and regenerate functional tissue, e.g. cardiac muscle cells after infarction, connective tissue fibroblasts and their extracellular matrix fill the void to form a scar. An exception is the central nervous system, where glial scars are formed after injury. Fibrob - last activity is influenced by various factors such as steroid hormone concentration, dietary content and prevalent mechanical stresses. Col - lagen formation is impaired in vitamin C deficiency. Adipocytes (lipocytes, fat cells) Adipocytes occur singly or in groups in many, but not all, connective tissues. They are numerous in adipose tissue ( Fig. 2.1 1). Individually, connective tissues, and so stabilize and orientate the tissue layers; may exert instructive effects on adjacent tissues, and so determine their polar - ity, rate of cell division, cell survival, etc.; and regulate angiogenesis. In addition, they may act as pathways for the migration and pathfinding activities of growing cell processes, both in development and in tissue repair, e.g. in guiding the outgrowth of axons and the re-establishment of neuromuscular junctions during regeneration after injury in the peripheral nervous system. Changes in basal lamina thickness are often associated with pathological conditions, e.g. the thickening of the glomerular basal lamina in glomerulonephritis and diabetes. CONNECTIVE AND SUPPORTING TISSUES The connective tissues are defined as those composed predominantly of intercellular material, the extracellular matrix, which is secreted mainly by the connective tissue cells. The cells are therefore usually widely separated by their matrix, which is composed of fibrous proteins and a relatively amorphous ground substance ( Fig. 2.9). Many of the special properties of connective tissues are determined by the composi - tion of the matrix, and their classification is also largely based on its characteristics. In some types of connective tissue, the cellular compo - nent eventually dominates the tissue, even though the tissue originally has a high matrix : cell ratio, e.g. adipose tissue. Connective tissues are derived from embryonic mesenchyme or, in the head region, largely from neural crest. Connective tissues have several essential roles in the body. These may be subdivided into structural roles, which largely reflect the special mechanical properties of the extracellular matrix components, and defensive roles, in which the cellular component has the dominant role. Connective tissues often also play important trophic and morphoge - netic parts in organizing and influencing the growth and differentiation of surrounding tissues, e.g. in the development of glands from an epi- thelial surface. Structural connective tissues are divided into ordinary (or general) types, which are widely distributed, and special skeletal types, i.e. car - tilage and bone, which are described in Chapter 5. A third type, haemo - lymphoid tissues, consists of peripheral blood cells, lymphoid tissues and their precursors; these tissues are described in Chapter 4. They are often grouped with other types of connective tissue because of their similar mesenchymal origins and because the various defensive cells of the blood also form part of a typical connective tissue cell population. They reach connective tissues via the blood circulation and migrate into them through the endothelial walls of vessels. CELLS OF GENERAL CONNECTIVE TISSUES Cells of general connective tissues can be separated into the resident cell population (fibroblasts, adipocytes, mesenchymal stem cells, etc.) and a population of migrant cells with various defensive functions (macrophages, lymphocytes, mast cells, neutrophils and eosinophils), which may change in number and moderate their activities according Fig. 2.9 General loose connective tissue (human), with bundles of collagen fibres (C) within an amorphous ground substance, penetrated by a neurovascular bundle of blood vessels (BV), lymphatics and nerves. A small autonomic ganglion is arrowed. (Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.) C BV BV Fig. 2.10 An electron micrograph of a fibroblast in human connective tissue, surrounded by bundles of finely banded collagen fibrils (shown at high magnification in the insert), which they secrete. (Courtesy of Dr Bart Wagner, Histopathology Department, Sheffield Teaching Hospitals, UK.)

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INTE gRATIN g CEllS INTO TISS uES 36 SECTION 1 nerve endings in adipose tissue is particularly important in this respect. No new adipose tissue is thought to form after the immediate postnatal period, and accumulation of body fat, as in obesity, is due to excessive accumulation of lipid in existing adipocytes, which become very large. Conversely, weight loss results from the mobilization and metabolism of lipid from adipocyte stores, with the consequent shrinkage of the cells. Mesenchymal stem cells Mesenchymal stem cells are normally inconspicuous cells in connective tissues. They are derived from embryonic mesenchyme and are able to differentiate into the mature cells of connective tissue during normal growth and development, in the turnover of cells throughout life and, most conspicuously, in the repair of damaged tissues in wound healing. There is emerging evidence that, even in mature tissues, mesenchymal stem cells remain pluripotent and able to give rise to all the resident cells of connective tissues in response to local signals and cues. The potential therapeutic use of mesenchymal stem cell-based therapy for a wide range of autoimmune disorders and degenerative diseases is reflected in a burgeoning literature in the field of translational medi - cine. (See, for example, Ankrum and Karp (2010), Jackson et al (2012) and Ren et al (2012)). Migrant cells Macrophages Macrophages are numerous in connective tissues, where they are either attached to matrix fibres or are motile and migratory ( Fig. 2.12). They are relatively large cells, 15–20 µm in diameter, with indented and rela- tively heterochromatic nuclei and a prominent nucleolus. Their cyto - plasm is slightly basophilic, contains many lysosomes and typically has a foamy appearance under the light microscope. Macrophages are important phagocytes and form part of the mononuclear phagocyte system. They can engulf and digest particulate organic materials, such as bacteria, and are able to clear dead or damaged cells from a tissue too. They are also the source of a number of secreted cytokines that have profound effects on many other cell types. Macrophages are able to proliferate in connective tissues to a limited extent, but are derived and replaced primarily from haemopoietic stem cells in the bone marrow, which circulate in the blood as monocytes before migrating through vessel walls into connective tissues, where they differentiate. Many properties of macrophages in general connective tissue are similar to those of related cells in other sites. These include: circulating monocytes, from which they are derived; alveolar macrophages in the the cells are oval or spherical in shape, but when packed together they are polygonal. They vary in diameter, averaging 50 µm. Each cell con - sists of a peripheral rim of cytoplasm, in which the nucleus is embed- ded, surrounding a single large central globule of fat, which consists of glycerol esters of oleic, palmitic and stearic acids. There is a small accu - mulation of cytoplasm around the oval nucleus, which is typically compressed against the cell membrane by the lipid droplet, together with the Golgi complex. Many cytoskeletal filaments, some endoplas - mic reticulum and a few mitochondria lie around the lipid droplet, which is in direct contact with the surrounding cytoplasm and not enclosed within a membrane. In sections of tissue not specially treated to preserve lipids, the lipid droplet is usually dissolved out by the sol - vents used in routine preparations, so that only the nucleus and the peripheral rim of cytoplasm surrounding a central empty space remain. Another form of adipose tissue, brown fat, occurs in the interscapu - lar region of neonates, a location it shares with the classic brown fat of rodents. Brown fat is characterized by the presence of large cells, each of which contains several separate droplets of fat (multilocular adipose tissue) rather than a single globule (typical of unilocular adipose tissue; see above), and by mitochondria in which the cristae are unusually large and numerous. White fat cells are specialized to store chemical energy, whereas the physiological role of brown adipose tissue (BAT) cells is to metabolize fatty acids and generate heat; BAT cells uncouple cellular respiration via the mitochondrial uncoupling protein UCP1. It had been thought that brown fat disappears during postnatal growth, but significant deposits of UCP1-positive brown fat have been detected by positron emission tomography (PET) scanning methods in adults, mainly in the supraclavicular region, in the neck and along the spine. Recent evidence suggests that these human UCP1-positive cells may not be classic brown fat cells but a distinct type of thermogenic fat cell called a beige fat cell, thought to be derived from precursor cells in white fat (Wu et al 2012). Such cells may represent an evolutionarily conserved cellular mechanism to provide flexibility in adaptive thermogenesis. It has long been recognized that adipose tissue is central to the control of energy balance and lipid homeostasis. There is a growing view that it may play a similarly important role as an endocrine organ, secreting a class of peptides called adipokines (Trayhurn and Wood 2004), which may enter the blood via capillaries or lymph. Different types of adipose tissue display functional and regional heterogeneity and differ in their involvement with disease processes (reviewed in Hassan et al (2012)). The mobilization of fat is under nervous or hor - monal control; noradrenaline (norepinephrine) released at sympathetic Fig. 2.11 Adipose tissue (human, from a lymph node specimen). Adipocytes (A) are distended polygonal cells filled with lipid, which has been extracted by the tissue processing. This leaves only the plasma membranes with scant cytoplasm and nuclei (arrows), occasionally visible compressed against the cell periphery. Small blood vessels (BV) penetrate the adipose tissue; larger vessels are seen on the right. (Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.) AA BV BVBV Fig. 2.12 Macrophages (M) in chronically inflamed human connective tissue, showing prominent pigmented, haemosiderin-containing cytoplasmic granules derived from ingested erythrocytes. Many are multinucleate. Also seen are plasma cells (P), small lymphocytes (L) and other haemopoietic cells. (Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.) LLM MPP P

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Connective and supporting tissues 37 CHAPTER 2 CELLS OF SPECIALIZED CONNECTIVE TISSUES Skeletal tissues – namely, cartilage and bone – are generally classified with the connective tissues, but their structure and functions are highly specialized and they are described in Chapter 5. As with the general connective tissues, these specialized types are characterized by their extracellular matrix, which forms the major component of the tissues and is responsible for their properties. The resident cells are different from those in general connective tissues. Cartilage is populated by chondroblasts, which synthesize the matrix, and by mature chondro- cytes. Bone matrix is elaborated by osteoblasts. Their mature progeny, osteocytes, are embedded within the matrix, which they help to min - eralize, turn over and maintain. A third cell type, the osteoclast, has a different lineage origin and is derived from haemopoietic tissue; osteo - clasts are responsible for bone degradation and remodelling in collabo - ration with osteoblasts. EXTRACELLULAR MATRIX The term extracellular matrix is applied collectively to the extracellular components of connective and supporting tissues. Essentially, it con- sists of a system of insoluble protein fibres, adhesive glycoproteins and soluble complexes composed of carbohydrate polymers linked to protein molecules (proteoglycans and glycosaminoglycans), which bind water. The extracellular matrix distributes the mechanical stresses on tissues and also provides the structural environment of the cells embedded in it, forming a framework to which they adhere and on which they can move (reviewed in Even-Ram and Yamada (2005) and Wolf and Friedl (201 1)). With the exception of bone matrix, it provides a highly hydrated medium, through which metabolites, gases and nutri - ents can diffuse freely between cells and the blood vessels traversing it or, in the case of cartilage, passing nearby. There are many complex interactions between connective tissue cells and the extracellular matrix. The cells continually synthesize, secrete, modify and degrade extracellular matrix components, and respond to contact with the matrix in the regulation of cell metabolism, prolifera - tion and motility. Degradation of the matrix is an important feature of embryonic development, morphogenesis, angiogenesis, tissue repair and remodelling (Mott and Werb 2004). Various types of proteinase are involved, principally metalloproteinases such as matrix metalloprotei - nases (MMPs), and those with a disintegrin and metalloproteinase domain (ADAMs) that include ADAMs with a thrombospondin domain (ADAMTS). Tissue remodelling depends on the controlled degradation of the extracellular matrix by secreted MMPs, regulated by their specific inhibitors, as occurs, for instance, during involution of the postpartum uterus or during menstrual lysis and shedding of the endometrium (Gaide Chevronnay et al 2012). In the process of matrix degradation, bioactive peptides are liberated that act as growth factors, cytokines and other signalling molecules to change the behaviour of cells in the vicin - ity. While precisely regulated under physiological conditions, patho - logically dysregulated extracellular matrix degradation is a cause of many diseases, such as atherosclerosis, emphysema, osteoarthritis and diabetic vascular complications. The insoluble fibres are mainly of two types of structural pro- tein: members of the collagen family, and elastin (Fig. 2.13). The lungs, which take up inhaled particles not cleared by the mucociliary rejection current; phagocytic cells in the lymph nodes, spleen and bone marrow; Kupffer cells of the liver sinusoids; and microglial cells of the central nervous system. Lymphocytes Lymphocytes are normally present in small numbers; they are numer - ous in general connective tissue only in pathological states, when they migrate in from adjacent lymphoid tissue or from the circulation. The majority are small cells (6–8 µm) with highly heterochromatic nuclei but they enlarge when stimulated. Two major functional classes exist, termed B and T lymphocytes. B lymphocytes originate in the bone marrow, then migrate to various lymphoid tissues, where they prolifer - ate. When antigenically stimulated, they undergo further mitotic divi - sions, then enlarge as they mature, commonly in general connective tissues, to form plasma cells that synthesize and secrete antibodies (immunoglobulins). Mature plasma cells are rounded or ovoid, up to 15 µm across, and have an extensive rough endoplasmic reticulum. Their nuclei are spherical, often eccentrically situated, and have a char - acteristic ‘clock-face’ configuration of heterochromatin (see Fig. 4.12) that is regularly distributed in peripheral clumps. The prominent Golgi complex is visible with a light microscope as a pale region to one side of the nucleus and the remaining cytoplasm is deeply basophilic because of the abundant rough endoplasmic reticulum. Mature plasma cells do not divide. T lymphocytes originate from precursors in bone marrow haemo - poietic tissue but later migrate to the thymus, where they develop T-cell identity, before passing into the peripheral lymphoid system, where they continue to multiply. When antigenically stimulated, T cells enlarge and their cytoplasm becomes filled with free polysome clusters. The functions of T lymphocytes are numerous: different subsets recog - nize and destroy virus-infected cells, tissue and organ grafts, or interact with B lymphocytes and several other defensive cell types. Mast cells Mast cells are important defensive cells. They occur particularly in loose connective tissues and in the fibrous capsules of certain organs such as the liver, and are numerous around blood vessels. Mast cells are round or oval, approximately 20 µm in diameter, with many filopodia extend - ing from the cell surface. The nucleus is centrally placed and relatively small. The cytoplasm contains large numbers of prominent vesicles and a well-developed Golgi apparatus, but scant endoplasmic reticulum. The vesicles have a high content of glycosaminoglycans and show a strongly positive reaction with the PAS stain for carbohydrates. They are membrane-bound, vary in size and shape (mean diameter 0.5 µm) and also have a rather heterogeneous content of dense, lipid-containing material, which may be finely granular, lamellar or in the form of membranous whorls. The major granule components, many of them associated with inflammation (Frenzel and Hermine 2013), are the proteoglycan heparin, histamine, tryptase, superoxide dismutase, aryl sulphatase, β-hexosaminidase and various other enzymes, including chymase in connective tissue but not mucosal mast cells, together with chemotactic factors for neutrophil and eosinophil granulocytes. There are functional differences between mast cells found in different tissues. Mast cells may be stimulated to release some or all of their contents, either by direct mechanical or chemical trauma, or after contact with particular antigens to which the body has previously been exposed. The consequences of granule release include alteration of capillary perme - ability, smooth muscle contraction, and activation and attraction to the locality of various other defensive cells. Responses to mast cell degranu - lation may be localized, e.g. urticaria, or there may occasionally be a generalized response to the release of large amounts of histamine into the circulation (anaphylactic shock). Mast cells closely resemble basophil granulocytes of the general circulation but are thought to develop as distinct descendants of an earlier myeloid lineage precursor. It is believed that they are generated in the bone marrow and circulate to the tissues as immature basophil-like cells, migrating through the capillary and venule walls to their final destination. For further reading, see Bischoff (2007) and Collington et al (201 1). Granulocytes (polymorphonuclear leukocytes) Neutrophil and eosinophil granulocytes are immigrant cells from the circulation. Relatively infrequent in normal connective tissues, their numbers may increase dramatically in infected tissues, where they are important components of cellular defence. Neutrophils are highly phagocytic, especially towards bacteria. The functions of eosinophils are less well understood. These cells are described further in Chapter 4. Fig. 2.13 Elastic fibres, seen as fine, dark, relatively straight fibres in a whole-mount preparation of mesentery, stained for elastin. The wavy pink bands are collagen bundles and oval grey nuclei are mainly of fibroblasts.

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INTE gRATIN g CEllS INTO TISS uES 38 SECTION 1 ency. Tendons, aponeuroses and ligaments are also highly ordered tissues (Ch. 5). Types II, III, V and XI collagens Types II, III, V and XI collagens can also aggregate to form linear fibrils. Type II collagen occurs in extremely thin (10 nm), short fibrils in the vitreous humour and in very thick fibrils in ageing human cartilage. The amino-acid sequence and banding pattern are very similar to those of type I collagen, as are the post-translational modifications of the triple helical protein molecule. The fine fibrils in the vitreous may fuse into thicker aggregates in older tissue. Type III collagen is very widely distributed, particularly in young and repairing tissues. It usually co-localizes with type I collagen, and cova- lent links between type I and type III collagen have been demonstrated. In skin, many fibrils are probably composites of type I and type III collagens. Reticular fibres Fine branching and anastomosing reticular fibres form the supporting mesh framework of many glands, including the liver ( Fig. 2.14), the kidney and lymphoreticular tissue (lymph nodes, spleen, etc.). Classi - cally, these fibres stained intensely with silver salts, although they are poorly stained using conventional histological techniques. They associ - ate with basal laminae and are often found in the neighbourhood of collagen fibre bundles. Reticular fibres are formed principally of type III collagen. Elastin Elastin is a 70 kDa protein, rich in the hydrophobic amino acids valine and alanine. Elastic fibrils, which also contain fibrillin, are highly cross-linked via two elastin-specific amino acids, desmosine and iso- desmosine, which are formed extracellularly from lysine residues. They are less widely distributed than collagen, yellowish in colour, typically cross-linked and usually thinner (10–20 nm) than collagen fibrils. They can be thick, e.g. in the ligamenta flava and ligamentum nuchae. Unlike collagen type I, they show no banding pattern in the electron micro - scope. They stain poorly with routine histological stains but are stained with orcein-containing preparations (see Fig. 2.13). They sometimes appear as sheets, as in the fenestrated elastic lamellae of the aortic wall. Elastin-rich structures stretch easily with almost perfect recoil, although they tend to calcify with age and lose elasticity. Elastin is highly resistant to attack by acid and alkali, even at high temperatures. Interfibrillar matrix Glycosaminoglycans The structural soluble polymers characteristic of the extracellular matrix are the acidic glycosaminoglycans, which are unbranched chains of repeating disaccharide units, each unit carrying one or more negatively charged groups (carboxylate or sulphate esters, or both). The anionic charge is balanced by cations (Na +, K+, etc.) in the interstitial fluid. Their polyanionic character endows the glycosaminoglycans with high osmotic activity, which helps to keep the fibrils apart, confers stiffness interfibrillar matrix (ground substance) includes a number of adhesive glycoproteins that perform a variety of functions in connective tissues, including cell–matrix adhesion and matrix–cell signalling. These glyco - proteins include fibronectin, laminin, tenascin and vitronectin, in addition to a number of other less well characterized proteins. The glycosaminoglycans of the interfibrillar matrix are, with one notable exception, post-translationally modified proteoglycan molecules in which long polysaccharide side chains are added to short core proteins during transit through the secretory pathway between the rough endo - plasmic reticulum and the trans-Golgi network. The exception, the poly - meric disaccharide, hyaluronan, has no protein core and is synthesized entirely by cell surface enzymes. For further reading on extracellular matrix molecules, see Pollard et al (2008). Functional attributes of con - nective tissues vary and depend on the abundance of its different com - ponents. Collagen fibres resist tension, whereas elastin provides a measure of resilience to deformation by stretching. The highly hydrated, soluble polymers of the interfibrillar material (proteoglycans and gly - cosaminoglycans, mainly hyaluronan) generally form a stiff gel resisting compressive forces. Thus tissues that are specialized to resist tensile forces (e.g. tendons) are rich in collagen fibrils; tissues that accommo - date changes in shape and volume (e.g. mesenteries) are rich in elastic fibres; and those that absorb compressive forces (e.g. cartilages) are rich in glycosaminoglycans and proteoglycans. In bone, mineral crystals take the place of most of the soluble polymers and endow the tissue with incompressible rigidity. Fibrillar matrix Collagens Collagens make up a very large proportion (approximately 30%) of all the proteins of the body. They consist of a wide range of related mol - ecules that have various roles in the organization and properties of connective (and some other) tissues. The first collagen to be character - ized was type I, the most abundant of all the collagens and a constituent of the dermis, fasciae, bone, tendon, ligaments, blood vessels and the sclera of the eyeball. The characteristic collagen of cartilage and the vitreous body of the eye, with a slightly different chemical composition, is type II, whereas type III is present in several tissues, including the dermis and blood vessels, and type IV is in basal lamina. The other types are widely distributed in various tissues. Five of the collagens, types I, II, III, V and XI, form fibrils; types IV, VIII and X form sheets or meshworks; types VI, VII, IX, XII, XIV and XVIII have an anchoring or linking role; and types XIII and XVII are transmembrane proteins. Biochemically, all collagens have a number of features in common. Unlike most other proteins, they contain high levels of hydroxyproline and all are composed of three polypeptides that form triple helices and are substantially modified post-translationally. After secretion, indi- vidual molecules are further cross-linked to form stable polymers. Func - tionally, collagens are structural proteins with considerable mechanical strength. Just a few of their distinguishing structural features are described below. For further reading on the molecular structure and functions of the collagens, see Pollard et al (2008). Type I collagen Type I collagen is very widely distributed. It forms inextensible fibrils in which collagen molecules (triple helices) are aligned side by side in a staggered fashion, with three-quarters of the length of each molecule in contact with neighbouring molecules. The fibril has well-marked bands of charged and uncharged amino acids arranged across it; these stain with heavy metals in a banding pattern that repeats every 65 nm in longitudinal sections viewed in the electron microscope (see Fig. 2.10 insert). Fibril diameters vary between tissues and with age. Developing tissues often have thinner fibrils than mature tissues. Corneal stroma fibrils are of uniform and thin diameter, whereas tendon fibrils may be up to 20 times thicker and quite variable. Tissues in which the fibrils are subject to high tensile loading tend to have thicker fibrils. Thick fibrils are composites of uniform thin fibrils with a diameter of 8–12 nm. The fibrils themselves are relatively flexible, but when mineralized (as in bone) or surrounded by high concentrations of proteo glycan (as in cartilage), the resulting fibre-reinforced composite materials are rigid. Fresh type I collagen fibres are tightly packed assemblies of parallel fibrils and are white and glistening. They form variably wavy (crimped) bundles of various sizes that are generally visible at the light microscope level. The component fibres may leave one bundle and interweave with others. In some situations, collagen fibrils are laid down in precise geo - metrical patterns, in which successive layers alternate in direction, e.g. corneal stroma, where the high degree of order is essential for transpar -Fig. 2.14 Reticular fibres (type III collagen; reticulin demonstrated by silver-staining) in human liver, forming a delicate meshwork within the space of Disse between hepatocytes (H), plasma membranes and the sinusoidal endothelia (S). (Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.) HH SS

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Connective and supporting tissues 39 CHAPTER 2 Tenascin Tenascin is large glycoprotein composed of six subunits that are joined at one end to form a structure that resembles the spokes of a wheel. There is a family of tenascin molecules, generated by alternative splicing of the tenascin gene transcript. Tenascin is abundant in embryonic tissues but its distribution is restricted in the adult. It appears to be important in guiding cell migration and axonal growth in early develop - ment: it may either promote or inhibit these activities, depending on the cell type and tenascin isoform. CLASSIFICATION OF CONNECTIVE TISSUES Connective and supporting tissues differ considerably in appearance, consistency and composition in different regions. These differences reflect local functional requirements and are related to the predomi - nance of the cell types; the concentration, arrangement and types of fibre; and the characteristics of the interfibrillar matrix. On these bases, general connective tissues can be classified into irregular and regular types, according to the degree of orientation of their fibrous components. Irregular connective tissues Irregular connective tissues can be further subdivided into loose, dense and adipose connective tissue. Loose (areolar) connective tissue Loose connective tissue is the most generalized form and is extensively distributed. Its chief function is to bind structures together, while still allowing a considerable amount of movement to take place. It consti - tutes the submucosa in the digestive tract and other viscera lined by mucosae, and the subcutaneous tissue in regions where this is devoid of fat (e.g. eyelids, penis, scrotum and labia), and it connects muscles, vessels and nerves with surrounding structures. It is present in the inte- rior of organs, where it binds together the lobes and lobules of glands, forms the supporting layer (lamina propria) of mucosal epithelia and vascular endothelia, and lies within and between fascicles of muscle and nerve fibres. Loose connective tissue consists of a meshwork of thin collagen and elastin fibres interlacing in all directions (see Fig. 2.13) to give a measure of both elasticity and tensile strength. The large meshes contain the soft, semi-fluid interfibrillar matrix or ground substance, and different con - nective tissue cells, which are scattered along the fibres or in the meshes. It also contains adipocytes, usually in small groups, and particularly around blood vessels. A variant of loose connective tissue occurs in the choroid and the sclera of the eye, where large numbers of pigment cells (melanocytes) are also present. Dense irregular connective tissue Dense irregular connective tissue is found in regions that are under considerable mechanical stress and where protection is given to ensheathed organs. The matrix is relatively acellular and contains a high proportion of collagen fibres organized into thick bundles interweaving in three dimensions and imparting considerable strength. There are few active fibroblasts, which are usually flattened with heterochromatic nuclei. Dense irregular connective tissue occurs in: the reticular layer of the dermis; the superficial connective tissue sheaths of muscle and nerves, and the adventitia of large blood vessels; and the capsules of various glands and organs (e.g. testis, sclera of the eye, periostea and perichondria). Adipose tissue A few adipocytes occur in loose connective tissue in most parts of the body. However, they constitute the principal component of adipose tissue (see Fig. 2.1 1), where they are embedded in a vascular loose con - nective tissue, usually divided into lobules by stronger fibrous septa carrying the larger blood vessels. Adipose tissue only occurs in certain regions. In particular it is found: in subcutaneous tissue; in the mesenter - ies and omenta; in the female breast; in bone marrow; as retro-orbital fat behind the eyeball; around the kidneys; deep to the plantar skin of the foot; and as localized pads in the synovial membrane of many joints. Its distribution in subcutaneous tissue shows characteristic age and sex differences. Fat deposits serve as energy stores, sources of meta - bolic lipids, thermal insulation (subcutaneous fat) and mechanical shock-absorbers (e.g. soles of the feet, palms of the hands, gluteal region and synovial membranes).on the porous gel that they collectively create, and gives the tissue a varying degree of basophilia. Glycosaminoglycans are named according to the tissues in which they were first found, e.g. hyaluronan (vitreous body), chondroitins (cartilage), dermatan (skin), keratan (cornea), heparan (liver). This terminology is no longer relevant, as most gly - cosaminoglycans are very widely distributed, whereas, conversely, some corneas contain little or no keratan sulphate. Of the glycosaminogly - cans, all except hyaluronan have short protein cores and are highly variable in their carbohydrate side-chain structure. Hyaluronan Hyaluronan was formerly called hyaluronic acid (or hyaluronate, as only the salt exists at physiological pH). It is a very large, highly hydrated molecule (25,000 kDa). Hyaluronan is found in all extracellular matri - ces and in most tissues, and is a prominent component of embryonic and developing tissues. Hyaluronan is important in the aggregation of proteoglycans and link proteins that possess specific hyaluronan binding sites (e.g. laminin). Indeed, the very large aggregates that are formed may be the essential compression-resisting units in cartilage. Hyaluronan also forms very viscous solutions, which are probably the major lubricants in synovial joints. Because of its ability to bind water, it is often present in semi-rigid structures (e.g. vitreous humour in the eye), where it cooperates with sparse but regular meshworks of thin collagen fibrils. Proteoglycans Proteoglycans have been classified according to the size of their protein core; their nomenclature is under review. The same core protein can bear different glycosaminoglycan side chains in different tissues. The functions of many proteoglycans are poorly understood. Some of the better-known proteoglycans are: aggrecan in cartilage, perlecan in basal laminae, decorin associated with fibroblasts in collagen fibril assembly, and syndecan in embryonic tissues. Adhesive glycoproteins These proteins include molecules that mediate adhesion between cells and the extracellular matrix, often in association with collagens, proteo - glycans or other matrix components. All of them are glycosylated and they are, therefore, glycoproteins. General connective tissue contains the well-known families of fibronectins (and osteonectin in bone), lam - inins and tenascins; there is a rapidly growing list of other glycoproteins associated with extracellular adhesion (Pollard et al 2008). They possess binding sites for other extracellular matrix molecules and for cell adhe - sion molecules, especially the integrins; in this way they enable cells selectively to adhere to and migrate through, appropriate matrix struc - tures (reviewed in Jacquemet et al (2013)). They also function as signal - ling molecules, which are detected by cell surface receptors and initiate changes within the cytoplasm (e.g. to promote the formation of hemidesmosomes or other areas of strong adhesion; reorganize the cytoskeleton; and promote or inhibit locomotion and cell division). Fibronectin Fibronectin is a large glycoprotein consisting of a dimer joined by disulphide links. Each subunit is composed of a string of large repetitive domains linked by flexible regions. Fibronectin subunits have binding sites for collagen, heparin and cell surface receptors, especially integrins, and so can promote adhesion between all these elements. In connective tissues, the molecules are able to bind to cell surfaces in an orderly fashion, to form short fibronectin filaments. The liver secretes a related protein, plasma fibronectin, into the circulation. The selective adhesion of different cell types to the matrix during development and in postna - tal life is mediated by numerous isoforms of fibronectin generated by alternative splicing. Isoforms found in embryonic tissues are also expressed during wound repair, when they facilitate tissue proliferation and cell movements; the adult form is re-expressed once repair is complete. laminin Laminin is a large (850 kDa) flexible molecule composed of three polypeptide chains (designated α, β and γ). There are many isoforms of the different chains, and at least 18 types of laminin. The prototypical molecule has a cruciform shape, in which the terminal two-thirds are wound round each other to form the stem of a cross, and the shorter free ends form the upright and transverse members. Laminin bears binding sites for other extracellular matrix molecules such as heparan sulphate, type IV collagen and entactin, and also for laminin receptor molecules (integrins) situated in cell plasma membranes. Laminin mol - ecules can assemble themselves into flat regular meshworks, e.g. in the basal lamina.

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INTE gRATIN g CEllS INTO TISS uES 40 SECTION 1 foci of stratified squamous metaplasia in response to irritants in ciga - rette smoke. Mesenchymal (osseous) metaplasia can occur, for example, in the fibrous connective tissue of muscles subjected to repeated damage, where trabeculi of bone develop. It is thought that stem cells (rather than the differentiated cells) in the affected tissue respond to changes in their environment by altering their differentiation pathway, a process that may be reversible if the stimulus is removed. MUCOSA (MUCOUS MEMBRANE) A mucosa or mucous membrane ( Fig 2.16) lines many internal hollow organs in which the inner surfaces are moistened by mucus, such as the intestines, conducting portions of the airway, and the genital and urinary tracts. A mucosa proper consists of an epithelial lining, which may have the ducts of mucosal, submucosal or extrinsic glands opening on to its surface, an underlying loose connective tissue, the lamina propria, and a thin layer of smooth muscle, the muscularis mucosae. This last layer either may be absent from some mucosae, or may be replaced by a layer of elastic fibres. The term mucous membrane reflects the fact that these tissues can all be peeled away as a sheet or membrane from underlying structures; the plane of separation occurs along the muscularis mucosae. Submucosa is a layer of supporting connective tissue that usually lies below the muscularis mucosae. It may contain mucous or seromucous submucosal glands. Inflammation of the viscera involves, primarily, the connective tissues of the submucosa and lamina propria, and is char - acterised by dilated vessels, oedema, and accumulations of extravasated immune defence cells. Most mucosae are also supported by one or more layers of smooth muscle, the muscularis externa. Contraction of this muscle may constrict the mucosal lumen (e.g. in the airway) or, where there are two or more muscle layers orientated in opposing directions (e.g. in the intestines), cause peristaltic movement of the viscus and the contents of its lumen. The outer surface of the muscle may be covered by a serosa or, where the structure is retroperitoneal or passes through the pelvic floor, by a connective tissue adventitia. MUCUS Mucus is a viscous suspension of complex glycoproteins (mucins) of various kinds, and is secreted by scattered individual epithelial (goblet) cells, a secretory surface epithelium (e.g. the stomach lining) or mucous and seromucous glands. The precise composition of the mucus varies with the tissue and secretory cells that produce it. All mucins consist of filamentous core proteins to which are attached carbohydrate chains, usually branched; salivary mucus contains nearly 600 chains. Carbohy - drate residues include glucose, fucose, galactose and N-acetylglucosamine (sialic acid). The terminals of some carbohydrate chains are identical to the blood group antigens of the ABO group in the majority of the population (secretors, bearing the secretor gene S e), and can be detected in salivary mucus by means of appropriate clinical tests. The long poly - meric carbohydrate chains bind water and protect surfaces against Regular connective tissues Regular connective tissues include highly fibrous tissues in which fibres are regularly orientated, either to form sheets such as fasciae and aponeuroses, or as thicker bundles such as ligaments or tendons ( Fig. 2.15). The direction of the fibres within these structures is related to the stresses that they undergo: fibrous bundles display considerable interweaving, even within tendons, which increases their structural sta - bility and resilience. The fibroblasts that secrete the fibres may eventually become trapped within the fibrous structure, where they become compressed, relatively inactive cells with stellate profiles and small heterochromatic nuclei; these cells are called tendon cells. Fibroblasts on the external surface may be active in continued fibre formation and they constitute a pool of cells available for repair of injured tissue. Although regular connective tissue is predominantly collagenous, some ligaments contain significant amounts of elastin, e.g. the liga - menta flava of the vertebral laminae and the vocal folds. The collagen fibres may form precise geometrical patterns, as in the cornea. Mucoid tissue Mucoid tissue is found chiefly as a stage in the development of connec - tive tissue from mesenchyme. It exists in Wharton’s jelly, which forms the bulk of the umbilical cord, and consists substantially of extracellular matrix, largely made up of hydrated mucoid material and a fine mesh - work of collagen fibres, in which nucleated, fibroblast-like cells with branching processes are found. Fibres are usually rare in typical mucoid tissue, although the full-term umbilical cord contains perivascular col - lagen fibres. Postnatally, mucoid tissue is seen in the pulp of a develop - ing tooth, the vitreous body of the eye (a persistent form of mucoid tissue that contains few fibres or cells) and the nucleus pulposus of the intervertebral disc. TRANSDIFFERENTIATION AND METAPLASIA Transitions occur between populations of cells forming an epithelium (sheets of polarized cells) and mesenchymal types (where the cells lack polarity) during normal development (see Thiery et al (2009)). In post - natal life, most well-described transitions between morphologically dif - ferent cell types do not cross an epithelial–mesenchymal boundary but are transitions between types of epithelial cell or, less frequently, between mesenchymal (connective tissue) cell types. Most instances of such transdifferentiation (metaplasia, see Commentary 1.4) are adaptive, to changing environmental conditions or trauma, and almost all are pathological; the altered cells are termed metaplastic. A very common and physiologically normal example is the squamous meta - plasia of columnar secretory epithelium of the distal endocervical canal, when exposed to the hormonally stimulated vaginal environment. Gastric metaplasia of the lower oesophagus may occur when chronic reflux of gastric juices exposes its stratified squamous epithelial lining to acid, and the original epithelium is replaced by a mucus-secreting columnar epithelium typical of the stomach (Barrett’s oesophagus); this is pathological and susceptible to malignant change. Similarly, the res - piratory epithelium (see Fig. 2.2D) of the upper airway often develops Fig. 2.15 Dense regular connective tissue in a tendon. Thick parallel bundles of type I collagen (here stained pink) give tendon its white colour in life. The elongated nuclei of inactive fibroblasts (tendon cells) are visible between collagen bundles. Fig. 2.16 A generalized mucosa and supporting tissues. For details and variations, see text. Mucosa SubmucosaEpithelium Lamina propria Muscularis mucosae Muscularis externa Submucosal glandDuct of extrinsic gland or organSerosa

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41 CHAPTER 2Key references FASCIA Fascia is a generic term applied to sheaths, sheets or other dissectible masses of connective tissue that are large enough to be visible to the unaided eye. The terms superficial fascia and deep fascia, widely used to describe the connective tissue between the skin and underlying muscle, and the connective tissue surrounding muscles, viscera and related structures, respectively, are no longer included in the Terminolo- gia Anatomica, although they remain in common usage in the English language. Tela subcutanea, hypodermis and subcutaneous tissue are the recommended synonymous terms that replace superficial fascia. Deeper-lying condensations of connective tissue have been defined according to their location, e.g. investing muscles (fascia musculorum) or viscera (fascia visceralis). Loosely packed connective tissue surrounds peripheral nerves, blood and lymph vessels as they pass between other structures, often linking them together as neurovascular bundles. Some large vessels, e.g. the common carotid and femoral arteries, are invested by a dense connective tissue sheath that may be functionally significant, aiding venous return by approximating large veins to pulsat - ing arteries.drying; they also provide good lubricating properties. In concentrated form, mucins form viscous layers that protect the underlying tissues against damage. Synthesis of mucus starts in the rough endoplasmic reticulum. It is then passed to the Golgi complex, where it is conjugated with sulphated carbohydrates to form the glycoprotein, mucinogen, and this is exported in small, dense, membrane-bound vesicles that swell as they approach the cell surface, with which they fuse before releasing their contents. SEROSA (SEROUS MEMBRANE) Serosa consists of a single layer of squamous mesothelial cells, express - ing keratin intermediate filaments, supported by an underlying layer of loose connective tissue that contains numerous blood and lymphatic vessels. Serosa lines the pleural, pericardial and peritoneal cavities, and covers the external surfaces of organs lying within those cavities and, in the abdomen, the mesenteries that envelop them. A potential space, filled with a small amount of protein-containing serous fluid – largely an exudate of interstitial fluid – exists between the outer parietal and the inner visceral layers of the serosa. KEY REFERENCES Collington SJ, Williams TJ, Weller CL 201 1 Innate immune cell trafficking: mechanisms underlying the localisation of mast cells in tissues. Trends Immunol 32:478–85.A discussion of recent advances in understanding the recruitment of mast cells to tissues. Duffield JS 2012 The elusive source of myofibroblasts: problem solved? Nat Med 18:1 178–80.A review of recent evidence for a perivascular cell (pericyte) origin for myofibroblasts and fibrotic tissue in a number of disease states. Frenzel L, Hermine O 2013 Mast cells and inflammation. Joint Bone Spine 80:141–5. A description of the role of mast cells in inflammatory processes and prospects for therapeutic intervention in inflammatory diseases. Hassan M, Latif N, Yacoub M 2012 Adipose tissue: friend or foe? Nature Rev Cardiol 9:689–702. A review of the status of adipose tissue, its structural and functional variations and roles in health and disease. Hinz B, Phan SH, Thannickal VJ et al 2012 Recent developments in myofi - broblast biology. Am J Path 180:1340–55. A review of recent work on myofibroblasts, their origins, molecular regulation of differentiation from precursor cells and roles in organ-specific fibrotic disease processes. McAnulty RJ 2007 Fibroblasts and myofibroblasts: their source, function and role in disease. Int J Biochem Cell Biol 39:666–71.A review of the biology of connective tissue fibroblasts and related mesenchymal cells. Pan X, Hobbs RP, Coulombe PA 2012 The expanding significance of keratin intermediate filaments in normal and diseased epithelia. Curr Opin Cell Biol 25:1–10.A discussion of the current understanding of the keratin intermediate filament family, specific to epithelia, and the roles of keratins in epithelial functions and selected diseases. Pollard TD, Earnshaw WC, Lippincott-Schwartz J 2008 Cell Biology, 2nd ed. Philadelphia: Elsevier, Saunders; Ch. 29 Extracellular matrix molecules, pp. 531–52.A comprehensive text on the molecular structures and functions of matrix molecules. Thiery JP, Acloque H, Huang RYJ et al 2009 Epithelial–mesenchymal transi - tions in development and disease. Cell 139:871–90.A description of these processes in normal development and the contribution of epithelial–mesenchymal transitions to carcinoma progression and metastasis. Wolf K, Friedl P 201 1 Extracellular matrix determinants of proteolytic and non-proteolytic cell migration. Trends Cell Biol 21:736–44.A review of cell migration through extracellular matrices in wound healing and pathological processes, using proteolytic and other mechanisms.

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Integrating cells into tissues 41.e1 CHAPTER 2 REFERENCES Ankrum J, Karp JM 2010 Mesenchymal stem cell therapy: two steps forward, one step back. Trends in Mol Med 16:203–9. Bischoff SC 2007 Role of mast cells in allergic and non-allergic immune responses: comparison of human and murine data. Nat Rev Immunol 7:93–104. Blanpain C, Horsley V, Fuchs E 2007 Epithelial stem cells: turning over new leaves. Cell 128:445–8. Collington SJ, Williams TJ, Weller CL 201 1 Innate immune cell trafficking: mechanisms underlying the localisation of mast cells in tissues. Trends Immunol 32:478–85.A discussion of recent advances in understanding the recruitment of mast cells to tissues. Duffield JS 2012 The elusive source of myofibroblasts: problem solved? Nat Med 18:1 178–80. A review of recent evidence for a perivascular cell (pericyte) origin for myofibroblasts and fibrotic tissue in a number of disease states. Even-Ram S, Yamada KM 2005 Cell migration in 3D matrix. Curr Opin Cell Biol 17:524–32. Frenzel L, Hermine O 2013 Mast cells and inflammation. Joint Bone Spine 80:141–5.A description of the role of mast cells in inflammatory processes and prospects for therapeutic intervention in inflammatory diseases. Gaide Chevronnay HP, Selvais C, Emonard H et al 2012 Regulation of matrix metalloproteinases activity studied in human endometrium as a para - digm of cyclic tissue breakdown and regeneration. Biochim Biophys Acta 1824:146–56. Hassan M, Latif N, Yacoub M 2012 Adipose tissue: friend or foe? Nature Rev Cardiol 9:689–702.A review of the status of adipose tissue, its structural and functional variations and roles in health and disease. Hinz B, Phan SH, Thannickal VJ et al 2012 Recent developments in myofi - broblast biology. Am J Path 180:1340–55.A review of recent work on myofibroblasts, their origins, molecular regulation of differentiation from precursor cells and roles in organ-specific fibrotic disease processes. Iozzo RV 2005 Basement membrane proteoglycans: from cellar to ceiling. Nat Rev Mol Cell Biol 6:646–56. Jackson WM, Nesti LJ, Tuan RS 2012 Concise review: clinical translation of wound healing therapies based on mesenchymal stem cells. Stem Cells Transl Med 1:44–50.Jacquemet G, Humphries MJ, Caswell PT 2013 Role of adhesion receptor trafficking in 3D cell migration. Curr Opin Cell Biol 25:1–6. McAnulty RJ 2007 Fibroblasts and myofibroblasts: their source, function and role in disease. Int J Biochem Cell Biol 39:666–71.A review of the biology of connective tissue fibroblasts and related mesenchymal cells. Mott JD, Werb Z 2004 Regulation of matrix biology by matrix metallopro - teinases. Curr Opin Cell Biol 16:558–64. Pan X, Hobbs RP, Coulombe PA 2012 The expanding significance of keratin intermediate filaments in normal and diseased epithelia. Curr Opin Cell Biol 25:1–10.A discussion of the current understanding of the keratin intermediate filament family, specific to epithelia, and the roles of keratins in epithelial functions and selected diseases. Pollard TD, Earnshaw WC, Lippincott-Schwartz J 2008 Cell Biology, 2nd ed. Philadelphia: Elsevier, Saunders; Ch. 29 Extracellular matrix molecules, pp. 531–52.A comprehensive text on the molecular structures and functions of matrix molecules. Ren G, Chen X, Dong F et al 2012 Concise review: mesenchymal stem cells and translational medicine: emerging issues. Stem Cells Transl Med 1:51–8. Stoeckelhuber M, Schubert C, Kesting MR et al 201 1 Human axillary apo - crine glands: proteins involved in the apocrine secretory mechanism. Histol Histopathol 26:177–84. Thiery JP, Acloque H, Huang RYJ et al 2009 Epithelial–mesenchymal transi - tions in development and disease. Cell 139:871–90.A description of these processes in normal development and the contribution of epithelial–mesenchymal transitions to carcinoma progression and metastasis. Trayhurn P, Wood IS 2004 Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 92:347–55. Wolf K, Friedl P 201 1 Extracellular matrix determinants of proteolytic and non-proteolytic cell migration. Trends Cell Biol 21:736–44.A review of cell migration through extracellular matrices in wound healing and pathological processes, using proteolytic and other mechanisms. Wu J, Bostro P, Sparks LM et al 2012 Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150:366–76.

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42 SECTION 1 CHAPTER 3 Nervous system with neurones in many different ways; their two-way communication is essential for normal brain activity. It was thought for many years that glia outnumbered neurones by 10 times in the CNS, but recent studies using the isotropic fractionator method have challenged that popular view, suggesting instead that the two cell populations are rather similar in size (Azevedo et al 2009). That said, the glia : neurone ratio has been reported to be as high as 17 : 1 in the thalamus (Pakkenberg and Gundersen 1988). The glial population in the CNS consists of microglia and macroglia; the latter are subdivided into oligodendrocytes and astrocytes. The principal glial cell in the PNS is the Schwann cell. Satellite cells sur - round each neuronal soma in ganglia. For further reading on the nervous system, see Finger (2001), Kandel et al (2012), Kettenmann and Ransom (2012), Levitan and Kaczmarek (2001), Nicholls et al (201 1) and Squire et al (2012). NEURONES Most of the neurones in the CNS are either clustered into nuclei, columns or layers, or dispersed within grey matter. Neurones in the PNS are confined to ganglia. Irrespective of location, neurones share many general features, which are discussed here in the context of central neurones. Special characteristics of ganglionic neurones and their adja- cent tissues are discussed on page 57. Neurones exhibit great variability in their size (cell bodies range from 5 to 100 µm diameter) and shape (Spruston 2008). Their surface areas are extensive because most neurones display numerous branched cell processes. They usually have a rounded or polygonal cell body (perikaryon or soma). This is a central mass of cytoplasm that encloses a nucleus and gives off long, branched extensions with which most intercellular contacts are made. Typically, one of these processes, the axon, is much longer than the others, the dendrites ( Fig. 3.2). Gener- ally, dendrites conduct electrical signals towards a soma whereas axons conduct impulses away from it. Neurones can be classified according to the number and arrange - ment of their processes (Bota and Swanson 2007). Multipolar neurones (Fig. 3.3) are common; they have an extensive dendritic tree that arises either from a single primary dendrite or directly from the soma, and a single axon. Bipolar neurones, which typify neurones of the special sensory systems, have only a single dendrite that emerges from the soma opposite the axonal pole. Unipolar neurones, which transmit general sensation, e.g. dorsal root ganglion neurones, have a single short process that bifurcates into a peripheral and a central process. This arrangement arises by the fusion of the proximal axonal and dendritic processes of a bipolar neurone during development, and so such neurones may also be termed pseudounipolar. Neurones may also be classified according to whether their axons terminate locally on other neurones (interneu - rones), or transmit impulses over long distances, often to distinct ter - ritories via defined tracts (projection neurones). Neurones are postmitotic cells and, with few exceptions, they are not replaced when lost. SOMA The plasma membrane of the soma is generally unmyelinated and is contacted by both inhibitory and excitatory axosomatic synapses; very occasionally, somasomatic and dendrosomatic contacts may be made. The non-synaptic surface may contain gap junctions and is partly covered by either astrocytic or satellite oligodendrocyte processes. The cytoplasm of a typical soma (see Fig. 3.2) is rich in rough and smooth endoplasmic reticulum and free polyribosomes, indicating a high level of protein synthetic activity. Free polyribosomes often The nervous system has two major divisions, the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the brain, spinal cord, optic nerve and retina, and contains the majority of neuronal cell bodies. The PNS includes all nervous tissue outside the CNS and consists of the cranial and spinal nerves, the peripheral auto - nomic nervous system (ANS) and the special senses (taste, olfaction, vision, hearing and balance). It is composed mainly of the axons of sensory and motor neurones that pass between the CNS and the body. The ANS is subdivided into sympathetic and parasympathetic compo - nents. It consists of neurones that innervate secretory glands and cardiac and smooth muscle, and is concerned primarily with control of the internal environment. Neurones in the wall of the gastrointestinal tract form the enteric nervous system (ENS) and are capable of sustaining local reflex activity that is independent of the CNS. The ENS contains as many intrinsic neurones in its ganglia as the entire spinal cord and is often considered as a third division of the nervous system (Gershon 1998). In the CNS, the cell bodies of neurones are often grouped together in discrete areas termed nuclei, or they may form more extensive layers or masses of cells; collectively they constitute the grey matter. Neuronal dendrites and synaptic contacts are mostly confined to areas of grey matter and form part of its meshwork of neuronal and glial processes, termed the neuropil. Their axons join bundles of nerve fibres that tend to be grouped separately to form tracts. In the spinal cord, cerebellum, cerebral cortices and some other areas, concentrations of tracts consti - tute the white matter, so called because the axons are often ensheathed in lipid-rich sheaths of myelin, which is white when fresh ( Fig. 3.1; see Fig. 16.9). The PNS is composed of the efferent axons (fibres) of motor neu - rones situated inside the CNS, and the cell bodies of sensory neurones (grouped together as ganglia) and their afferent processes. Sensory cells in dorsal root ganglia give off both centrally and peripherally directed processes; there are no synapses on their cell bodies. Also included are ganglionic neurones of the ANS, which receive synaptic contacts from the peripheral fibres of preganglionic autonomic neurones whose cell bodies lie within the CNS. For further details of the organization of the nervous system, see Chapter 16. When the neural tube is formed during prenatal development (Sanes et al 201 1), its walls thicken greatly but do not completely obliterate the cavity within. The latter remains in the spinal cord as the narrow central canal and becomes greatly expanded in the brain to form a series of interconnected cavities called the ventricular system. In the fore- and hindbrains, parts of the neural tube roof do not generate neurones but become thin, folded sheets of secretory tissue, which are invaded by blood vessels and are called the choroid plexuses. The latter secrete cerebrospinal fluid (CSF), which fills the ventricles and subarachnoid spaces, and penetrates the intercellular spaces of the brain and spinal cord to create their interstitial fluid. The CNS has a rich blood supply, which is essential to sustain its high metabolic rate. The blood–brain barrier places considerable restrictions on the substances that are able to diffuse from the blood stream into the neuropil. Neurones encode information, conduct it over considerable dis- tances, and then transmit it to other neurones or to various non-neural targets such as muscle cells. The propagation of this information within the nervous system depends on rapid electrical signals, the action potentials. Transmission to other cells is mediated by secretion of neu - rotransmitters at special junctions, either with other neurones (syn - apses), or with cells outside the nervous system, e.g. muscle cells at neuromuscular junctions, gland cells or adipose tissue, and causes changes in the behaviour of the target cells. The nervous system contains large populations of non-neuronal cells, termed neuroglia or glia. These cells do not generate action poten - tials, but convey information encoded as transient changes in intracel-lular calcium concentration, termed calcium signalling. Glia interact

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Nervous system 42.e1 CHAPTER 3 Fig. 3.1 A section through the human cerebellum stained to show the arrangement in the brain of the central white matter (WM, deep pink) and the highly folded outer grey matter (GM). In the cerebellum, GM consists of an inner granular layer of tightly packed small neurones (blue) and an outermost molecular layer (pale pink), where neuronal processes make synaptic contacts. (Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.) WM GM

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Neurones 43 CHAPTER 3 tide subunits, NF-L (68 kDa), NF-M (160 kDa) and NF-H (200 kDa). NF-M and NF-H have long C-terminal domains that project as side arms from the assembled neurofilament and bind to neighbouring filaments. They can be heavily phosphorylated, particularly in the highly stable neurofilaments of mature axons, and are thought to give axons their tensile strength. Some axons are almost filled by neurofilaments. Microtubules are important in axonal transport, although dendrites usually have more microtubules than axons. Centrioles persist in mature postmitotic neurones, where they are concerned with the gen - eration of microtubules rather than cell division. Centrioles are associ - ated with cilia on the surfaces of developing neuroblasts. Their significance, other than at some sensory endings (e.g. the olfactory mucosa), is not known. Pigment granules ( Fig. 3.5) appear in certain regions, e.g. neurones of the substantia nigra contain neuromelanin, which is probably a waste product of catecholamine synthesis. A similar pigment gives a bluish colour to the neurones in the locus coeruleus. Some neurones are unusually rich in metals, which may form components of enzyme systems, e.g. zinc in the hippocampus and iron in the red nucleus. Ageing neurones, especially in spinal ganglia, accumulate granules of lipofuscin (senility pigment) in residual bodies, which are lysosomes packed with partially degraded lipoprotein material. DENDRITES Dendrites are highly branched, usually short processes that project from the soma (see Fig. 3.2; Shah et al 2010). The branching patterns of many dendritic arrays are probably established by random adhesive interac - tions between dendritic growth cones and afferent axons that occur during development. There is an overproduction of dendrites in early development, and this is pruned in response to functional demand as the nervous system matures and information is processed through the dendritic tree. There is evidence that dendritic trees may be plastic structures throughout adult life, expanding and contracting as the traffic of synaptic activity varies through afferent axodendritic contacts (for a review, see Wong and Ghosh (2002)). Groups of neurones with similar functions have a similar stereotypic tree structure ( Fig. 3.6), suggesting that the branching patterns of dendrites are important determinants of the integration of the afferent inputs that converge on the tree. For a review of current research on dendritic trees in the normal and patho - logical brain, see Kulkarni and Firestein (2012). Dendrites differ from axons in many respects. They represent the afferent rather than the efferent system of the neurone, and receive both excitatory and inhibitory axodendritic contacts. They may also make dendrodendritic and dendrosomatic connections (see Fig. 3.9), some of which are reciprocal. Synapses occur either on small projections called dendritic spines or on the smooth dendritic surface. Dendrites contain ribosomes, smooth endoplasmic reticulum, microtubules, neu - rofilaments, actin filaments and Golgi complexes. Their neurofilament proteins are poorly phosphorylated and their microtubules express the microtubule-associated protein (MAP)-2 almost exclusively in compari- son with axons. The shapes of dendritic spines range from simple protrusions to structures with a slender stalk and expanded distal end. Most spines are not more than 2 µm long, and have one or more terminal expansions; they can also be short and stubby, branched or bulbous. Large mush - room spines are assumed to have differentiated in response to afferent activity (‘memory spines’; Matsuzaki et al 2004). These large spines often contain a spine apparatus, an organelle consisting of small sacs of endoplasmic reticulum interleaved by electron-dense bars (Gray 1959, Segal et al 2010). Mouse mutants deficient in these organelles show memory deficits (Deller et al 2003). Free ribosomes and polyri - bosomes are concentrated at the base of the spine. Ribosomal accumu - lations near synaptic sites provide a mechanism for activity-dependent synaptic plasticity through the local regulation of protein synthesis. AXONS The axon originates either from the soma or from the proximal segment of a dendrite at a specialized region free of Nissl granules, the axon hillock (see Fig. 3.2). Action potentials are initiated here, at the junction with the proximal axon (axon initial segment). The axonal plasma membrane (axolemma) is undercoated at the hillock by a concentration of cytoskeletal molecules, including spectrin and actin fibrils, which are important in anchoring numerous voltage-sensitive channels to the membrane. For details, see Bender and Trussell (2012), and for neural electrophysiological techniques, see Sakmann and Neher (2009). The congregate in large groups associated with the rough endoplasmic retic - ulum. These aggregates of RNA-rich structures are visible by light micro - scopy as basophilic Nissl bodies or granules. They are distributed throughout the cell body and large dendrites; the axon hillock is con - spicuously ribosome-free. Nissl bodies are more obvious in large, highly active cells, such as spinal motor neurones (Fig. 3.4), which contain large stacks of rough endoplasmic reticulum and polyribosome aggre - gates. Maintenance and turnover of cytoplasmic and membranous com-ponents are necessary activities in all cells; the huge total volume of cytoplasm within the soma and processes of many neurones requires a considerable commitment of protein synthetic machinery. Neurones also synthesize other proteins (enzyme systems, G-protein coupled receptors, scaffold proteins) involved in the production of neurotrans - mitters and in the reception and transduction of incoming stimuli. Various transmembrane channel proteins and enzymes are located at the surfaces of neurones, where they are associated with movements of ions. The nucleus is characteristically large and euchromatic, and contains at least one prominent nucleolus; these are features typical of all cells engaged in substantial levels of protein synthesis. The cytoplasm con - tains many mitochondria and moderate numbers of lysosomes. Golgi complexes are usually close to the nucleus, near the bases of the main dendrites and opposite the axon hillock. The neuronal cytoskeleton is a prominent feature of its cytoplasm and gives shape, strength and support to the dendrites and axons. A number of neurodegenerative diseases are characterized by abnormal aggregates of cytoskeletal proteins (reviewed in Cairns et al (2004)). Neurofilaments (the intermediate filaments of neurones) and microtu - bules are abundant in the soma and along dendrites and axons; the proportions vary with the type of neurone and cell process. Bundles of neurofilaments constitute neurofibrils, which can be seen by light microscopy in silver-stained or immunolabelled sections. Neurofila - ments are heteropolymers of proteins assembled from three polypep-Fig. 3.2 A schematic view of typical neurones featuring one with the soma cut away to show the nucleus and cytoplasmic organelles, dendritic trees with synaptic contacts, other types of synapse, the axon hillock and a myelinated axon. Soma Nucleolus Nucleus Axon hillock Dendrite Axon Myelin sheath Axon collateral Axo-axonal synapseAxodendritic synapse Axosomatic synapse Synaptic terminals

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NERvOuS SySTEm 44 SECTION 1 Fig. 3.5 Neurones in the substantia nigra of the human midbrain, showing cytoplasmic granules of neuromelanin pigment. (Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.) Fig. 3.3 The variety of shapes of neurones and their processes. The inset shows a human multipolar retinal ganglion cell, filled with fluorescent dye by microinjection. (Inset, Courtesy of Drs Richard Wingate, James Morgan and Ian Thompson, King’s College, London.) Smooth muscle e.g intestine Striated (skeletal) muscleUnipolar neurone Peripheral axonSensory endings e.g. in skin Bipolar neurone Soma Axon Soma Central axonSensory Integrative Motor Apical dendrites Pyramidal cell soma Axon Interneurone AxonSomaBasal dendrites AxonDendrites Purkinje cell soma AxonNissl bodies in soma SomaLarge motorneurone AxonPresynaptic autonomic neurone Soma Postsynaptic autonomic neuroneAxon Interneurone Fig. 3.4 Spinal motor neurones (toluidine blue stained resin section, rat tissue) showing a group of cell bodies (somata, S), some with the proximal parts of axonal and dendritic processes (P) visible. Their nuclei (N) typically have prominent, deeply staining nucleoli, indicative of metabolically highly active cells; two are visible in the plane of section. Nissl granules (G) are seen in the cytoplasm. Surrounding the neuronal somata is the neuropil, consisting of the interwoven processes of these and other neurones and of glial cells. S GN P P

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Neurones 45 CHAPTER 3 role in Alzheimer’s disease (Cairns et al 2004): formation of tau oli - gomers and the subsequent pathological filament arrays are critical steps in the aetiopathogenesis of this condition. Neurofilament proteins ranging from high to low molecular weights are highly phosphorylated in mature axons, whereas growing and regenerating axons express a calmodulin-binding membrane-associated phosphoprotein, growth- associated protein-43 (GAP-43), as well as poorly phosphorylated neurofilaments. Neurones respond differently to injury, depending on whether the damage occurs in the CNS or the PNS. The glial microenvironment of a damaged central axon does not facilitate axonal regrowth; conse - quently, reconnection with original synaptic targets does not normally occur. In marked contrast, the glial microenvironment in the PNS is capable of facilitating axonal regrowth. However, functional outcome of clinical repair of a large mixed peripheral nerve, especially if the injury occurs some distance from the target organ, or produces a long defect in the damaged nerve, is frequently unsatisfactory (Birch 201 1; see also Commentary 1.6 ). Axoplasmic flow Neuronal organelles and cytoplasm are in continual motion. Bidirec - tional streaming of vesicles along axons results in a net transport of materials from the soma to the terminals, with more limited movement in the opposite direction. Two major types of transport occur, one slow and one relatively fast. Slow axonal transport is a bulk flow of axoplasm only in the anterograde direction, carrying cytoskeletal proteins and soluble, non-membrane-bound proteins from the soma to the termi - nals at a rate of approximately 0.1–3 mm a day. In contrast, fast axonal transport carries membrane-bound vesicular material (endosomes and lysosomal autophagic vacuoles) and mitochondria at approximately 200 mm a day in the retrograde direction (towards the soma) and approximately 40 mm per day anterogradely (in particular, synaptic vesicles containing neurotransmitters). Rapid flow depends on microtubules. Vesicles with side projections line up along microtubules and are transported along them by their side arms. Two microtubule-based motor proteins with adenosine 5 ′- triphosphatase (ATPase) activity are involved in fast transport: kinesin family proteins are responsible for the fast component of anterograde transport, and cytoplasmic dynein is responsible for retrograde trans - port. Retrograde transport mediates the movement of neurotrophic viruses, e.g. herpes zoster, rabies and polio, from peripheral terminals, and their subsequent concentration in the neuronal soma. It has been suggested that specific pools of endocytic organelles, signalling endo - somes, mediate the long-distance axonal transport of growth factors, such as neurotrophins and their signalling receptors. Defects in axonal and dendritic transport have been linked to various neurodegenerative processes. See Guzik and Goldstein (2004), Hinckelmann et al (2013) and Schmieg et al (2014) for reviews of axonal transport in health and disease. SYNAPSES Transmission of impulses across specialized junctions (synapses) between two neurones is largely chemical and depends on the release of neurotransmitters from the presynaptic terminal. These neurotrans - mitters bind to cognate receptors in the postsynaptic neuronal mem - brane, resulting in a change of membrane conductance and leading to either a depolarization or a hyperpolarization (Ryan and Grant 2009). The patterns of axonal termination vary considerably. A single axon may synapse with one neurone (e.g. climbing fibres ending on cere - bellar Purkinje neurones), or more often with many neurones (e.g. cerebellar parallel fibres, which provide an extreme example of this phenomenon). In synaptic glomeruli (e.g. in the olfactory bulb), groups of synapses between two or many neurones form interactive units encapsulated by neuroglia ( Fig. 3.7 ; Perea et al 2009). Electrical synapses (direct communication via gap junctions) are rare in the human CNS and are confined largely to groups of neurones with tightly coupled activity, e.g. the inspiratory centre in the medulla. They will not be discussed further here. Classification of chemical synapses Chemical synapses have an asymmetric structural organization ( Figs 3.8–3.9) in keeping with the unidirectional nature of their transmis- sion. Typical chemical synapses share a number of important features. They all display an area containing a presynaptic density apposed to a axon hillock is unmyelinated and often participates in inhibitory axo- axonal synapses. It is unique because it contains ribosomal aggregates immediately below the postsynaptic membrane (Kole and Stuart 2012). In the CNS, small, unmyelinated axons lie free in the neuropil, whereas in the PNS they are embedded in Schwann cell cytoplasm. Myelin, which is formed around almost all axons of >2 µm diameter by oligodendrocytes in the CNS and by Schwann cells in the PNS, begins at the distal end of the axon hillock. Nodes of Ranvier are spe - cialized regions of myelin-free axon where action potentials are gener - ated and where an axon may branch. In both CNS and PNS, the territory of a myelinated axon between adjacent nodes is called an internode; the region close to a node, where the myelin sheath terminates, is called the paranode; and the region just beyond that is the juxtaparanode. Myelin thickness and internodal lengths are, in general, positively cor - related with axon diameter. The density of sodium channels in the axolemma is highest at nodes of Ranvier, and very low along internodal membranes; sodium channels are spread more evenly within the axo - lemma of unmyelinated axons. Fast potassium channels are present in the paranodal regions of myelinated axons. Fine processes of glial cyto- plasm (astrocytic in the CNS, Schwann cell in the PNS) surround the nodal axolemma. The terminals of an axon are unmyelinated. Most expand into presy- naptic boutons, which may form connections with axons, dendrites, neuronal somata or, in the periphery, muscle fibres, glands and lym - phoid tissue. Exceptions include the free afferent sensory endings in, for example, the epidermis, which are unspecialized structurally, and the peripheral terminals of afferent sensory fibres with encapsulated endings (see Fig. 3.27). Axon terminals contain abundant small clear synaptic vesicles and large dense-core vesicles. The former contain a neurotransmitter (e.g. glutamate, γ-aminobutyric acid (GABA), acetyl - choline) that is released into the synaptic cleft on the arrival of an action potential at the terminal and which then binds to cognate receptors on the postsynaptic membrane. Depending on the nature of the transmit - ter and its receptors, the postsynaptic neurone will become excited or inhibited. The dense-core vesicles contain neuropeptides, including brain-derived neurotrophic factor (BDNF; Dieni et al 2012). Axon ter - minals may themselves be contacted by other axons, forming axo- axonal presynaptic inhibitory circuits. Further details of neuronal microcircuitry are given in Kandel et al (2012) and Haines (2006). Axons contain microtubules, neurofilaments, mitochondria, mem - brane vesicles, cisternae and lysosomes. They do not usually contain ribosomes or Golgi complexes, other than at the axon hillock; excep - tionally, the neurosecretory fibres of hypothalamo-hypophysial neu - rones contain the mRNA of neuropeptides. Organelles are differentially distributed along axons, e.g. there is a greater density of mitochondria and membrane vesicles in the axon hillock, at nodes and in presynaptic endings. Axonal microtubules are interconnected by cross-linking MAPs, of which tau is the most abundant. Microtubules have an intrin - sic polarity, and in axons all microtubules are uniformly orientated with their rapidly growing ends directed away from the soma towards the axon terminal. The microtubule binding protein tau plays an important Fig. 3.6 A Purkinje neurone from the cerebellum of a rat stained by the Golgi–Cox method, showing the extensive two-dimensional array of dendrites. (Courtesy of Dr Martin Sadler and Professor M Berry, Division of Anatomy and Cell Biology, GKT School of Medicine, London.)

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NERvOuS SySTEm 46 SECTION 1 corresponding postsynaptic density; the two are separated by a narrow (20–30 nm) gap, the synaptic cleft. Synaptic vesicles containing the appropriate neurotransmitter are found on the presynaptic side, clus - tered near the presynaptic density at the presynaptic membrane. Together these define the active zone, the area of the synapse where neurotransmission takes place (Eggermann et al 2012, Gray 1959). Chemical synapses can be classified according to a number of dif- ferent parameters, including the neuronal regions forming the synapse, their ultrastructural characteristics, the chemical nature of their neurotransmitter(s) and their effects on the electrical state of the post - synaptic neurone. The following classification is limited to associations between neurones. Neuromuscular junctions share many (though not all) of these parameters, and are often referred to as peripheral synapses. They are described separately on page 63. Synapses can occur between almost any surface regions of the par- ticipating neurones. The most common type occurs between an axon and either a dendrite or a soma, when the axon is expanded as a small bulb or bouton (see Figs 3.8–3.9). This may be a terminal of an axonal branch (terminal bouton) or one of a row of bead-like endings, when the axon makes contact at several points, often with more than one neurone (bouton de passage). Boutons may synapse with dendrites, including thorny protrusions named dendritic spines or the flat surface of a dendritic shaft; a soma (usually on its flat surface, but occasionally on spines); the axon hillock; and the terminal boutons of other axons. The connection is classified according to the direction of transmis - sion, and the incoming terminal region is named first. Most common are axodendritic synapses, although axosomatic connections are fre - quent. All other possible combinations are found but are less common, i.e. axo-axonal, dendro-axonal, dendrodendritic, somatodendritic or somatosomatic. Axodendritic and axosomatic synapses occur in all regions of the CNS and in autonomic ganglia, including those of the ENS. The other types appear restricted to regions of complex inter - action between larger sensory neurones and microneurones, e.g. in the thalamus. Ultrastructurally, synaptic vesicles may be internally clear or dense, and of different size (loosely categorized as small or large) and shape (round, flat or pleomorphic, i.e. irregularly shaped). The submembra - nous densities may be thicker on the postsynaptic than on the presyn - aptic side (asymmetric synapses), or equivalent in thickness (symmetrical synapses), and can be perforated or non-perforated. Synaptic ribbons Fig. 3.7 The arrangement of a complex synaptic unit. A cerebellar synaptic glomerulus with excitatory (‘ +’) and inhibitory (‘ −’) synapses grouped around a central axonal bouton. The directions of transmission are shown by the arrows. +–+– +– + Neuroglial cellAxon of Golgi cell Soma of granule cell Mossy fibre axon terminalDendrite ofGolgi cell Fig. 3.8 Electron micrographs demonstrating various types of synapse. A, A cross-section of a dendrite (D) on which two synaptic boutons (B) end. The upper bouton contains round vesicles, and the lower bouton contains flattened vesicles of the small type. A number of pre- and postsynaptic (P) thickenings mark the specialized zones of contact. B, A type I synapse (S, postsynaptic site) containing both small, round, clear vesicles and also large, dense-cored vesicles of the neurosecretory type. C, A large terminal bouton (B) of an optic nerve afferent fibre, which is making contact with a number of postsynaptic processes, in the dorsal lateral geniculate nucleus of the rat. One of the postsynaptic processes (*) also receives a synaptic contact from a bouton (Bf) containing flattened vesicles. D, Reciprocal synapses (S) between two neuronal processes in the olfactory bulb. (Courtesy of Professor AR Lieberman, Department of Anatomy, University College, London.) ** A BC DPP BB B Bf S SSDP PP BB B Bf S SSD

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Neurones 47 CHAPTER 3 instances, types I and II synapses are found in close proximity, orien - tated in opposite directions across the synaptic cleft (a reciprocal synapse). Mechanisms of synaptic activity Synaptic activation begins with arrival of one or more action potentials at the presynaptic bouton, which causes the opening of voltage-sensitive calcium channels in the presynaptic membrane. The response time in typical fast-acting synapses is then very rapid; classic neurotransmitter (e.g. ACh, glutamate or GABA) is released in less than a millisecond. Release-ready synaptic vesicles are docked to the presynaptic membrane and primed through processes not yet fully understood. On Ca2+ influx through voltage-sensitive channels, their membranes fuse to open a pore through which neurotransmitter diffuses into the synaptic cleft (Eggermann et al 2012; Gray 1959). Once the vesicle has discharged its contents, its membrane is incor - porated into the presynaptic plasma membrane and is then recycled back into the bouton by endocytosis near the edges of the active zone. The recycling time for a synaptic vesicle may be in the range of a few seconds to minutes; newly recycled vesicles may be used instantly for the next cycle of neurotransmitter release (cycling pool of vesicles). The fusion of vesicles with the presynaptic membrane is responsible for the observed quantal behaviour of neurotransmitter release, both during neural activation and spontaneously, in the slightly leaky resting condi - tion (Neher and Sakaba 2008; Suedhof 2012). Postsynaptic events vary greatly, depending on the receptor mole - cules and their related molecular complexes (Murakoshi and Yasuda 2012). Receptors are generally classed as either ionotropic or metabo- tropic. Ionotropic receptors are multimeric protein complexes that harbour intrinsic ion channels that can be operated by conformational changes induced when neurotransmitter molecules bind the receptor complex, causing a voltage change within the postsynaptic cell. Exam - ples are the nicotinic ACh receptor and the related GABA A receptor, which are formed from five subunits, and the tetrameric ionotropic glutamate receptors, such as the N-methyl-D-aspartate (NMDA) receptor or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. Alternatively, the receptor and ion channel may be separate molecules, coupled by G-proteins, some via a complex cascade of chemical interactions (a second messenger system), e.g. the adenylate cyclase pathway. Postsynaptic effects are generally rapid and short-lived, because the transmitter is quickly inactivated either by an extracellular enzyme (e.g. acetylcholinesterase, AChE), or by uptake into neurones or glial cells. Examples of such metabotropic receptors are the mus - carinic ACh receptor and the dopamine receptor. Neurohormones Neurohormones are included in the class of molecules with neurotransmitter-like activity. They are synthesized in neurones and released into the blood circulation by exocytosis at synaptic bouton-like are found at sites of neurotransmission in the retina and inner ear. They have a distinctive morphology, in that the synaptic vesicles are grouped around a ribbon- or rod-like density orientated perpendicular to the cell membrane (see Fig. 3.9). Synaptic boutons make obvious close contacts with postsynaptic structures but many other terminals lack specialized contact zones. Areas of transmitter release occur in the varicosities of unmyelinated axons, where effects are sometimes diffuse, e.g. the aminergic pathways of the basal ganglia, and in autonomic fibres in the periphery. In some instances, such axons may ramify widely throughout extensive areas of the brain and affect the behaviour of very large populations of neu - rones, e.g. the diffuse cholinergic innervation of the cerebral cortices. Pathological degeneration of these pathways can therefore cause wide - spread disturbances in neural function. Neurones express a variety of neurotransmitters, either as one class of neurotransmitter per cell or more often as several. Good correlations exist between some types of transmitter and specialized structural features of synapses. In general, asymmetric synapses with relatively small spherical vesicles are associated with acetylcholine (ACh), gluta - mate, serotonin (5-hydroxytryptamine, 5-HT) and some amines; those with dense-core vesicles include many peptidergic synapses and other amines (e.g. noradrenaline (norepinephrine), adrenaline (epine - phrine), dopamine). Symmetrical synapses with flattened or pleomor- phic vesicles have been shown to contain either GABA or glycine. Neurosecretory endings found in various parts of the brain and in neuroendocrine glands and cells of the dispersed neuroendocrine system share many features with presynaptic boutons. They all contain peptides or glycoproteins within dense-core vesicles. The latter are of characteristic size and appearance: they are often ellipsoidal or irregular in shape, and relatively large, e.g. oxytocin and vasopressin vesicles in the neurohypophysis may be up to 200 nm in diameter. Synapses may cause depolarization or hyperpolarization of the post - synaptic membrane, depending on the neurotransmitter released and the classes of receptor molecule in the postsynaptic membrane. Depo- larization of the postsynaptic membrane results in excitation of the postsynaptic neurone, whereas hyperpolarization has the effect of tran - siently inhibiting electrical activity. Subtle variations in these responses may also occur at synapses where mixtures of neuromediators are present and their effects are integrated. For details of the synaptic organ - ization of the brain, see Shepherd (2003). Type I and II synapses There are two broad categories of synapse, type I and type II. In active zones of type I synapses the cytoplasmic density is thicker on the post-synaptic side. In type II synapses the pre- and postsynaptic densities are thinner and more symmetrical. Type I boutons contain a predominance of small spherical vesicles approximately 50 nm in diameter, and type II boutons contain oval or flattened vesicles. Throughout the CNS, type I synapses are generally excitatory and type II are inhibitory. In a few Fig. 3.9 The structural arrangements of different types of synaptic contact. Excitatory synapses Serial synapses Axosomatic synapses Bouton de passageA With small clear spherical vesiclesWith dense catecholamine- containing vesiclesExcitatory to dendriteInhibitory axo-axonal synapse With small flattened vesiclesWith large flattened vesiclesInhibitory to dendrite Excitatory in opposite direction Neurosecretory ending Reciprocal synapse Inhibitory synapsesDendriteCapillaryB C Ribbon synapse Retinal rodAxo-initial segment synapseNucleus

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NERvOuS SySTEm 48 SECTION 1 lie mainly in the brainstem, although their axons ramify widely into all parts of the nervous system. Monoaminergic cells are also present in the retina. Noradrenaline is the chief transmitter present in sympathetic gangli - onic neurones with endings in various tissues, notably smooth muscle and glands, and in other sites including adipose and haemopoietic tissues and the corneal epithelium. It is also found at widely distributed synaptic endings within the CNS, many of them the terminals of neu - ronal somata situated in the locus coeruleus in the medullary floor. The actions of noradrenaline depend on its site of action and vary with the type of postsynaptic receptor, e.g. it strongly inhibits neurones of the submucosal plexus of the intestine and of the locus coeruleus via α 2-adrenergic receptors, whereas it mediates depolarization, producing vasoconstriction, via β-receptors in vascular smooth muscle. Adrenaline is present in central and peripheral nervous pathways and occurs with noradrenaline in the suprarenal medulla. Both adrenaline and noradrenaline are found in dense-cored synaptic vesicles approximately 50 nm in diameter. Dopamine is a neuromediator of considerable clinical importance, found mainly in neurones with cell bodies in the telencephalon, diencephalon and mesencephalon. A major dopaminergic neuronal population in the midbrain constitutes the substantia nigra, so called because its cells contain neuromelanin, a black granular by-product of dopamine synthesis. Dopaminergic endings are particularly numer-ous in the corpus striatum, limbic system and cerebral cortex. Structur - ally, dopaminergic synapses contain numerous dense-cored vesicles that resemble those containing noradrenaline. Pathological reduction in dopaminergic activity has widespread effects on motor control, affective behaviour and other neural activities, as seen in Parkinson’s syndrome. Serotonin and histamine are found in neurones mainly within the CNS. Serotonin is typically synthesized in small midline neuronal clus - ters in the brainstem, mainly in the raphe nuclei; the axons from these neurones ramify extensively throughout the entire brain and spinal cord. Synaptic terminals contain rounded, clear vesicles approximately 50 nm in diameter and are of the asymmetrical type. Histaminergic neurones appear to be relatively sparse and are restricted largely to the hypothalamus. Amino acids There are three major amino acids: GABA, glutamate and glycine, which bind to specific receptors (Barrera and Edwardson 2008). GABA is a major inhibitory transmitter released at the terminals of local circuit neurones within the brainstem and spinal cord (e.g. the recurrent inhib - itory Renshaw loop), cerebellum (where it is the main transmitter of Purkinje cells), basal ganglia, cerebral cortex, thalamus and subthala- mus. It is stored in flattened or pleomorphic vesicles within symmetrical synapses. GABA may be inhibitory to postsynaptic neurones, or may mediate either presynaptic inhibition or facilitation, depending on the synaptic arrangement (Gassmann and Bettler 2012). Glutamate is the major excitatory transmitter present widely within the CNS, including the major projection pathways from the cortex to the thalamus, tectum, substantia nigra and pontine nuclei. It is found in the central terminals of the auditory and trigeminal nerves, and in the terminals of parallel fibres ending on Purkinje cells in the cerebel - lum. Structurally, glutamate is associated with asymmetrical synapses containing small (approximately 30 nm), round, clear synaptic vesicles (Contractor et al 201 1). For further reading, see Willard and Koochek - pour (2013). Glycine is a well-established inhibitory transmitter of the CNS, par - ticularly the lower brainstem and spinal cord, where it is mainly found in local circuit neurones. Recent evidence suggests that glycine may also be released from glutamatergic axon terminals to participate in activa - tion of NMDA receptors, and from astrocytes into the synaptic cleft via activation of non-NMDA-type glutamatergic ionotropic receptors in the glial cell membrane (see Harsing and Matyus (2013) for further references). ATP and adenosine ATP serves not only as a universal energy substrate, but also as an extra - cellular signalling molecule. Specific ionotropic (P2X) and metabo- tropic (P2Y) receptors are expressed in neurones and even more prominently on all types of glial cell. Adenosine is a degradation product of ATP and has specific metabotropic receptors that may be located presynaptically (Burnstock et al 201 1). Nitric oxide Nitric oxide (NO) is of considerable importance at autonomic and enteric synapses, where it mediates smooth muscle relaxation. It structures. As with classic endocrine gland hormones, they may act at great distances from their site of secretion. Neurones secrete into the CSF or local interstitial fluid to affect other cells, either diffusely or at a distance. To encompass this wide range of phenomena the general term neuromediation has been used, and the chemicals involved are called neuromediators. Neuromodulators Some neuromediators do not appear to affect the postsynaptic mem - brane directly but they can affect its responses to other neuromediators, either enhancing their activity (by increasing or prolonging the immedi - ate response), or perhaps limiting or inhibiting their action. These substances are called neuromodulators. A single synaptic terminal may contain one or more neuromodulators in addition to a neurotransmit - ter, usually (though not always) in separate vesicles. Neuropeptides (see below) are nearly all neuromodulators, at least in some of their actions. They are stored within dense granular synaptic vesicles of various sizes and appearances. Development and plasticity of synapses Embryonic synapses first appear as inconspicuous dense zones flanking synaptic clefts. Immature synapses often appear after birth, suggesting that they may be labile, and are reinforced if transmission is function- ally effective, or withdrawn if redundant. This is implicit in some theo - ries of memory (Squire and Kandel 2008), which postulate that synapses are modifiable by frequency of use, to establish preferential conduction pathways. Evidence from hippocampal neurones suggests that even brief synaptic activity can increase the strength and sensitivity of the synapse for some hours or longer (long-term potentiation, LTP). During early postnatal life, the normal developmental increase in numbers and sizes of synapses and dendritic spines depends on the degree of neural activity and is impaired in areas of damage or functional deprivation. Neurotransmitter molecules Until recently, the molecules known to be involved in chemical syn - apses were limited to a fairly small group of classic neurotransmitters, e.g. ACh, noradrenaline (norepinephrine), adrenaline (epinephrine), dopamine and histamine, all of which had well-defined rapid effects on other neurones, muscle cells or glands. However, many synaptic interactions cannot be explained on the basis of classic neurotransmit - ters, and it is now known that other substances, particularly some amino acids such as glutamate, glycine, aspartate, GABA and the monoamine, serotonin, also function as transmitters. Substances first identified as hypophysial hormones or as part of the dispersed neuroen - docrine system (see below) of the alimentary tract, can be detected widely throughout the CNS and PNS, often associated with functionally integrated systems. Many of these are peptides; more than one hundred (together with other candidates) function mainly as neuromodulators and influence the activities of classic transmitters. Acetylcholine Acetylcholine (ACh) is perhaps the most extensively studied neuro - transmitter of the classic type. Its precursor, choline, is synthesized in the neuronal soma and transported to the axon terminals, where it is acetylated by the enzyme choline acetyl transferase (ChAT), and stored in clear spherical vesicles 40–50 nm in diameter. ACh is synthesized by motor neurones and released at all their motor terminals on skeletal muscle. It is released by preganglionic fibres at synapses in parasympa - thetic and sympathetic ganglia, and many parasympathetic, and some sympathetic, ganglionic neurones are cholinergic. ACh is also associ - ated with the degradative extracellular enzyme AChE, which inactivates the transmitter by converting it to choline. The effects of ACh on nicotinic receptors (i.e. those in which nicotine is an agonist) are rapid and excitatory. In the CNS, the nicotinic ACh receptor mediates the effect of tobacco (for review, see Albuquerque et al (2009)). In the peripheral autonomic nervous system, the slower, more sustained excitatory effects of cholinergic autonomic endings are mediated by muscarinic receptors via a second messenger system. Monoamines Monoamines include the catecholamines (noradrenaline (norepine - phrine), adrenaline (epinephrine) and dopamine), the indoleamine serotonin (5-hydroxytryptamine, 5-HT) and histamine (Haas et al 2008). They are synthesized by neurones in sympathetic ganglia and by their homologues, the chromaffin cells of the suprarenal medulla and paraganglia. Within the CNS, the somata of monoaminergic neurones

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Central glia 49 CHAPTER 3 ASTROCYTES Astrocytes are the most abundant and diverse glial cell type but their identity is not well defined (Matyash and Kettenmann 2010). There is no common marker that labels all astrocytes, in the way that myelin basic protein is a marker for oligodendrocytes or the calcium-binding protein Iba1 is a marker for microglia. A commonly used marker is the expression of glial fibrillary acidic protein (GFAP), which forms inter - mediate filaments, but GFAP is not expressed in all astrocytes. The morphology of astrocytes is extremely diverse. Classically, two forms were distinguished: protoplasmic and fibrous astrocytes. Proto - plasmic astrocytes (star-shaped cells) are found in grey matter, possess several stem processes that branch further into a very complex network, and contact synapses, both at the pre- and postsynaptic membranes. Fibrous astrocytes are predominantly found in white matter and their processes are often orientated in parallel with the axons. Radial glial cells are found early in development and serve as stem cells for neu - rones and glial cells. They may be categorized as astrocytes because they transform later in development into typical astrocytes. There are a number of other types of astrocyte with specialized morphologies. Berg - mann glial cells in the cerebellum have somata in the Purkinje cell layer, processes that intermingle with the dendritic trees of the Purkinje neurones and terminal end-feet at the pial surface. Müller cells in the retina have a radial morphology and span the entire retina. Other astrocytic cells are tanycytes, velate astrocytes (cerebellum) and pitui - cytes (infundibulum and neurohypophysis of the pituitary gland). Pituicyte processes end mostly on endothelial cells in the neurohypo - physis and tuber cinereum. Astrocyte complexity and morphological diversity has reached the highest evolutionary level in humans ( Fig. 3.1 1). A single astrocyte may enwrap several neuronal somata and make contacts with tens of thou - sands of individual synapses; bipolar astrocytes located in layer 5 and 6 of the cortex may extend processes up to 1 mm long. Astrocytes in grey matter form a syncytium in which cells are inter - connected by gap junctions, permitting the exchange of ions (e.g. calcium, propagated in waves) and small molecules such as ATP or glucose. They are the only cells in the brain capable of converting glucose into glycogen, which serves as an energy store. Before re-releasing glucose, astrocytes convert it to lactate, which is taken up by neurones; failure in glucose flow through the astrocytic network results in impair - ment of neuronal function. Astrocytes not only respond to neuronal activity but also modulate that activity. They enwrap all penetrating and intracerebral arterioles and capillaries, control the ionic and metabolic environment of the neuropil and mediate neurovascular coupling. They form specialized structures that contact either the pial surface (as the glia limitans) or blood vessels; their end-feet entirely enwrap blood vessels and are instrumental in the induction of the blood–brain barrier. Traumatic injury to the CNS induces astrogliosis, seen as a local increase in the number and size of GFAP-positive cells and a character - istic extensive meshwork of processes. The microenvironment of this glial scar, which may also include cells of oligodendrocyte lineage and myelin debris, plays an important role in inhibiting regrowth of damaged CNS axons (Robel et al 201 1, Seifert et al 2006). functions in several types of synaptic plasticity, including hippocampal long-term potentiation (LTP), when it may act as a retrograde messen - ger after postsynaptic NMDA receptor activation. NO is able to diffuse freely through cell membranes, and so is not under such tight quantal control as vesicle-mediated neurotransmission. Neuropeptides Many neuropeptides coexist with other neuromediators in the same synaptic terminals. As many as three peptides often share a particular ending with a well-established neurotransmitter, in some cases within the same synaptic vesicles. Some peptides occur in both the CNS and the PNS, particularly in the ganglion cells and peripheral terminals of the ANS, whilst others are entirely restricted to the CNS. Only a few examples are given here. Most of the neuropeptides are classified according to the site where they were first discovered. For example, the gastrointestinal peptides were initially found in the gut wall, and a group that includes releasing hormones, adenohypophysial and neurohypophysial hormones was first associated with the pituitary gland. Some of these peptides are closely related to each other in their chemistry because they are derived from the same gene products (e.g. the pro-opiomelanocortin group), which are cleaved to produce smaller peptides. Substance P (SP) was the first of the peptides to be characterized as a gastrointestinal neuromediator and is considered to be the proto - typic neuropeptide. It is an 1 1-amino-acid polypeptide that belongs to the tachykinin neuropeptide family, and is a major neuromediator in the brain and spinal cord. Contained within large granular synaptic vesicles, SP is found in approximately 20% of dorsal root and trigemi - nal ganglion cells, in particular in small nociceptive neurones, and in some fibres of the facial, glossopharyngeal and vagal nerves. Within the CNS, SP is present in several apparently unrelated major pathways, and has been described in the limbic system, basal ganglia, amygdala and hypothalamus. Its known action is prolonged postsynaptic excitation, particularly from nociceptive afferent terminals, which sus - tains the effects of noxious stimuli. SP is one of the main neuropep - tides that trigger an inflammatory response in the skin and has also been implicated in the vomiting reflex, changes in cardiovascular tone, stimulation of salivary secretion, smooth muscle contraction, and vasodilation. Vasoactive intestinal polypeptide (VIP), another gastrointestinal peptide, is widely present in the CNS, where it is probably an excitatory neurotransmitter or neuromodulator. It is found in distinctive bipolar neurones of the cerebral cortex; small dorsal root ganglion cells, par - ticularly of the sacral region; the median eminence of the hypothala - mus, where it may be involved in endocrine regulation; intramural ganglion cells of the gut wall; and sympathetic ganglia. Somatostatin (ST, somatotropin release inhibiting factor) has a broad distribution within the CNS, and may be a central neurotransmit - ter or neuromodulator. It also occurs in small dorsal root ganglion cells. Beta-endorphin, leu- and metenkephalins, and the dynorphins belong to a group of peptides called the naturally occurring opiates that possess analgesic properties. They bind to opiate receptors in the brain where, in general, their action seems to be inhibitory. Enkephalins have been localized in many areas of the brain. Their particular localization in the septal nuclei, amygdaloid complex, basal ganglia and hypothalamus suggests that they are important mediators in the limbic system and in the control of endocrine function. They have also been implicated strongly in the central control of pain pathways, because they are found in the peri-aqueductal grey matter of the midbrain, a number of reticu - lar raphe nuclei, the spinal nucleus of the trigeminal nerve and the substantia gelatinosa of the spinal cord. The enkephalinergic pathways exert an important presynaptic inhibitory action on nociceptive affer - ents in the spinal cord and brainstem. Like many other neuromediators, enkephalins also occur widely in other parts of the brain in lower concentrations. CENTRAL GLIA Glial (neuroglial) cells (Fig 3.10) vary considerably in type and number in different regions of the CNS. There are two major groups, macroglia (astrocytes and oligodendrocytes) and microglia, classified according to origin. Macroglia arise within the neural plate, in parallel with neu - rones, and constitute the great majority of glial cells. Their functions are diverse and are now known to extend beyond a passive supporting role (reviewed in Kettenmann and Ransom (2012)). Microglia have a small soma (see Fig. 3.19) and are derived from a distinct lineage of monocytic cells originating from the yolk sac.Fig. 3.10 The different types of non-neuronal cell in the CNS and their structural organization and interrelationships with each other and with neurones. Pia materSubpial end-foot Oligodendrocyte Capillary Myelinated axonAstrocyteAstrocytePerineuronal end-foot Pericapillary end-footMicroglial cellTanycyte Ependymal cell VentricleNeurone

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Nervous system 49.e1 CHAPTER 3 Astrocytes control the diameter of the vessels they contact and can trigger either their dilation or their contraction, depending on the sub - stances they release and the levels of associated neuronal activity. They express water channels (aquaporins) at the end-feet covering the capil - laries; it has been suggested that this may represent the means by which astrocytes control brain volume (Tait et al 2008), and it may be relevant to understanding mechanisms of brain tissue swelling, a major clinical complication. Astrocytes express different glutamate transporters that efficiently maintain low levels of extracellular glutamate, which is excitotoxic. Internalized glutamate is converted into glutamine and released from astrocytes to be taken up by local neurones and recon - verted to glutamate via the glutamate–glutamine cycle. They play a similar role in controlling extracellular GABA levels via expression of GABA transporters. Astrocytes possess both passive and active mecha - nisms to control extracellular potassium levels at a resting level of about 3 mmol. They also express transporters that regulate pH and are thought to play an important role in controlling extracellular pH in the brain. For further reading on the concept of the ‘tripartite synapse’, where astrocytic processes interact with pre- and postsynaptic neuronal ele - ments, see Haydon and Carmignoto (2006). It has become evident that astrocytes are involved in the modulation of long-term potentiation (considered as a cellular mechanism of memory formation) and heterosynaptic depression. They modulate neuronal activity by releasing neuroactive substances such as D-serine, ATP or glutamate; it is unclear whether they express all the elements required for neurotransmitter release by a vesicular mechanism (Parpura and Zorec 2010).

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NERvOuS SySTEm 50 SECTION 1 which means that a free exchange of molecules occurs between blood and adjacent brain. Most of these areas are situated close to the ventri - cles and are known as circumventricular organs; these areas make up less than 1% of the total area of the brain. Elsewhere, unrestricted diffusion through the blood–brain barrier is only possible for sub-stances that can cross biological membranes because of their lipophilic character. Lipophilic molecules may be actively re-exported by the brain endothelium. Breakdown of the blood–brain barrier occurs when the brain is damaged by ischaemia or infection, and is also associated with primary and metastatic cerebral tumours. Reduced blood flow to a region of the brain alters the permeability and regulatory transport functions of the barrier locally; the increased stress on compromised endothelial cells results in leakage of fluid, ions, serum proteins and intracellular sub - stances into the extracellular space of the brain. The integrity of the barrier can be evaluated clinically using computed tomography and functional magnetic resonance imaging. Breakdown of the blood–brain barrier may be seen at postmortem in jaundiced patients who have had an infarction. Normally, the brain, spinal cord and peripheral nerves remain unstained by the bile post mortem, although the choroid plexus is often stained a deep yellow. However, areas of recent infarction (1–3 days) will also be stained by bile pigment because of the localized breakdown of the blood–brain barrier. OLIGODENDROCYTES Oligodendrocytes myelinate CNS axons and are most commonly seen as intrafascicular cells in myelinated tracts ( Figs 3.13–3.14). They usually have round nuclei and their cytoplasm contains numerous mitochondria, microtubules and glycogen. They display a spectrum of morphological variation, from cells with large euchromatic nuclei and pale cytoplasm, to cells with heterochromatic nuclei and dense cyto - plasm. In contrast to Schwann cells, which myelinate only one axonal segment, individual oligodendrocytes myelinate up to 50 axonal seg - ments. Some oligodendrocytes are not associated with axons, and are either precursor cells or perineuronal (satellite) oligodendrocytes with processes that ramify around neuronal somata. Within tracts, interfascicular oligodendrocytes are arranged in long rows interspersed at regular intervals with single astrocytes. Since oli - godendrocyte processes are radially aligned to the axis of each row, myelinated tracts typically consist of cables of axons myelinated by a row of oligodendrocytes running down the axis of each cable. Oligodendrocytes originate from the ventricular neurectoderm and the subependymal layer in the fetus, and continue to be generated from the subependymal plate postnatally. Stem cells migrate and seed into white and grey matter to form a pool of adult progenitor cells, which can later differentiate to replenish defunct oligodendrocytes, and pos - sibly remyelinate axons in pathologically demyelinated regions. These cells display a highly branching morphology and express a specific chondroitin sulphate proteoglycan (Neuron Glia 2 (NG2) in rats and its homologue, melanoma cell surface chondroitin sulphate proteo - glycan (MSCP), in humans). The name NG2 cell is used to describe the cells in both species: several different names have also been used since it was first recognized, including polydendrocyte (Nishiyama et al 2009) and syantocyte (Butt et al 2005). NG2 cells express a complex set of voltage-gated channels and ionotropic receptors for glutamate Blood–brain barrier Proteins circulating in the blood enter most tissues of the body except those of the brain, spinal cord and peripheral nerves. This concept of a blood–brain or a blood–nerve barrier applies to many substances – some are actively transported across the blood–brain barrier, others are actively excluded. The blood–brain barrier is located at the capillary endothelium within the brain and is dependent on the presence of tight junctions (occluding junctions, zonulae adherentes) between endothe - lial cells coupled with a relative lack of transcytotic vesicular transport. The tightness of the barrier is substantially supported by the close apposition of astrocytes, which direct the formation of endothelial tight junctions, to blood capillaries (reviewed in Abbott et al (2006), Cardoso et al (2010); Fig. 3.12). The blood–brain barrier develops during embryonic life but may not be fully completed by birth. There are certain areas of the adult brain where the endothelial cells are not linked by tight junctions, Fig. 3.11 Human protoplasmic astrocytes are larger and more complicated than their rodent counterparts. A, A typical mouse protoplasmic astrocyte. Glial fibrillary acidic protein (GFAP) immunostain; white. SB = 20 µm. B, A typical human protoplasmic astrocyte to the same scale. SB = 20 µm. (From Oberheim NA, Takano T, Han X, et al 2009 Uniquely hominid features of adult human astrocytes. J Neurosci 29:3276–87.) A B Fig. 3.12 The relationship between the glia limitans, perivascular cells and blood vessels within the brain, in longitudinal ( A) and transverse (B) sections. A sheath of astrocytic end-feet wraps around the vessel and, in vessels larger than capillaries, its investment of pial meninges. Vascular endothelial cells are joined by tight junctions and supported by pericytes; perivascular macrophages lie outside the endothelial basal lamina (light blue). Astrocyte end-foot Basal lamina Pia mater (larger vessels only) Pericyte under the basal lamina Perivascular cell (macrophage) Endothelium Basal laminaPericyte Astrocyte end-footA B

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Central glia 51 CHAPTER 3 and GABA; they form direct synapses with axons, enabling transient activation of these receptors (Hill and Nishiyama 2014). There is con - siderable support for the view that the NG2 cell is a distinct glial type. Nodes of Ranvier and incisures of Schmidt–Lanterman The territory ensheathed by an oligodendrocyte (or Schwann cell) process defines an internode, the interval between internodes is called a node of Ranvier (Fig. 3.15) and the territory immediately adjacent to the nodal gap is a paranode, where loops of oligodendrocyte cytoplasm abut the axolemma. Nodal axolemma is contacted by fine filopodia of perinodal cells, which have been shown in animal studies to have a presumptive adult oligodendrocyte progenitor phenotype; their func - tion is unknown. Schmidt–Lanterman incisures are helical decompac - tions of internodal myelin where the major dense line of the myelin sheath splits to enclose a spiral of oligodendrocyte cytoplasm. Their structure suggests that they may play a role in the transport of molecules across the myelin sheath, but their function is not known. MYELIN AND MYELINATION Myelin is formed by oligodendrocytes (CNS) and Schwann cells (PNS). A single oligodendrocyte may ensheathe up to 50 separate axon seg - ments, depending on calibre, whereas myelinating Schwann cells ensheathe axons on a 1 : 1 basis. In general, myelin is laid down around axons above 2 µm in diam - eter. However, the critical minimal axon diameter for myelination is smaller and more variable in the CNS than in the PNS (approximately 0.2 µm in the CNS compared with 1–2 µm in the PNS). There is con - siderable overlap between the size of the smallest myelinated and the largest unmyelinated axons, and so axonal calibre is unlikely to be the only factor in determining myelination. Moreover, the first axons to become ensheathed ultimately attain larger diameters than those that are ensheathed at a later date. There is a reasonable linear relationship between axon diameter and internodal length and myelin sheath thick - ness: as the sheath thickens from a few lamellae to up to 200, the axon may also grow from 1 to 15 µm in diameter. Internodal lengths increase about 10-fold during the same time (Nave 2010). It is not known precisely how myelin is formed in either PNS or CNS. Akt/mTOR (mammalian (or mechanistic) target of rapamycin) signalling has emerged as one of the major pathways involved in myeli - nation; it has been implicated in the regulation of several steps during the development of myelinating Schwann cells and oligodendrocytes (Norrmén and Suter 2013). In the CNS, myelination also depends in part on expression of a protein (Wiskott–Aldrich syndrome protein family verprolin homologous; WAVE), which influences the actin cytoskeleton, oligodendrocyte lamellipodia formation and myelination (Kim et al 2006). The ultrastructural appearance of myelin is usually explained in terms of the spiral wrapping of an extensive, flat glial process (lamellipodium) around an axon, and the subsequent extrusion of cytoplasm from the sheath at all points other than incisures and paranodes. In this way, the compacted external surfaces of the plasma membrane of the ensheathing glial cell are thought to produce the minor dense lines, and the compacted inner cytoplasmic surfaces, the major dense lines, of the mature myelin sheath (Fig. 3.16). These lines, first described in early electron microscope studies of the myelin sheath, correspond to the intraperiod and period lines respectively, defined in X-ray studies of myelin. The inner and outer zones of occlusion of the spiral process are continuous with the minor dense line and are called Fig. 3.13 The ensheathment of a number of axons by the processes of an oligodendrocyte. The oligodendrocyte soma is shown in the centre and its myelin sheaths are unfolded to varying degrees to show their extensive surface area. (Modified from Morell P, Norton WT (1980, May). Myelin, Scientific American, 242(5), 88–90, 92, 96 and Raine CS (1984), Morphology of Myelin and Myelination. In Myelin, 2nd ed. P Morell (ed) New York (Plenum Press), by permission.)Node of Ranvier NucleusOligodendrocyte Outer loopLateral loop Axon Longitudinal incisuresInner loop Myelin sheath Fig. 3.14 A, An oligodendrocyte enwrapping several axons with myelin, demonstrated in a whole-mounted rat anterior medullary velum, immunolabelled with antibody to an oligodendrocyte membrane antigen. B, A confocal micrograph of a mature myelin-forming oligodendrocyte in an adult rat optic nerve, iontophoretically filled with an immunofluorescent dye by intracellular microinjection. (A, Courtesy of Fiona Ruge. B, Prepared by Professor A Butt, Portsmouth, and Kate Colquhoun, formerly Division of Physiology, GKT School of Medicine, London.) A BFig. 3.15 A node of Ranvier (N) in the central nervous system of a rat. The pale-staining axon (A) is ensheathed by oligodendrocyte myelin (arrow), apart from a short, exposed region at the node. Toluidine blue stained resin section. (Courtesy of Dr Clare Farmer, King’s College, London.) A N

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NERvOuS SySTEm 52 SECTION 1 ependymal lining of the ventricles but four major types have been described. These are: general ependymal, which overlies grey matter; general ependymal, which overlies white matter; specialized areas of ependyma in the third and fourth ventricles; and choroidal epithelium. The ependymal cells overlying areas of grey matter are cuboidal. Each cell bears approximately 20 central apical cilia, surrounded by short microvilli. The cells are joined by gap junctions and desmosomes. Beneath them there may be a subependymal (or subventricular) zone, from two to three cells deep, consisting of cells that generally resemble ependymal cells. In rodents, the subventricular zone contains neural progenitor cells, which can give rise to new neurones, but the existence of these stem cells in the adult human brain is controversial (Sanai et al 201 1, Kempermann 201 1). The capillaries beneath the ependymal cells have no fenestrations and few transcytotic vesicles, which is typical of the CNS. Where the ependyma overlies myelinated tracts of white matter, the cells are much flatter and few are ciliated. There are gap junctions and desmosomes between these cells, but their lateral margins interdigitate, unlike their counterparts overlying grey matter. No sub - ependymal zone is present. Specialized areas of ependymal cells called the circumventricular organs are found in four areas around the margins of the third ventricle: namely, the lining of the median eminence of the hypothalamus; the subcommissural organ; the subfornical organ; and the vascular organ of the lamina terminalis. The area postrema, at the inferoposterior limit of the fourth ventricle, has a similar structure. In all of these sites the ependymal cells are only rarely ciliated and their ventricular surfaces bear many microvilli and apical blebs. They have numerous mitochon - dria, well-formed Golgi complexes and rather flattened basal nuclei. They are joined laterally by tight junctions, which form a barrier to the passage of materials across the ependyma, and by desmosomes. Many of the cells are tanycytes (ependymal astrocytes) and have basal processes that project into the perivascular space surrounding the underlying capillaries. Significantly, these capillaries are fenestrated and therefore do not form a blood–brain barrier. It is believed that neu - ropeptides can pass from nervous tissue into the CSF by active transport through the ependymal cells in these specialized areas, and so access a wide population of neurones via the permeable ependymal lining of the rest of the ventricle. The ependyma is highly modified where it lies adjacent to the vas - cular layer of the choroid plexuses.the inner and outer mesaxons. For further reading on aspects of myeli - nation, see Bakhti et al (2013). There are significant differences between central and peripheral myelin, reflecting the fact that oligodendrocytes and Schwann cells express different proteins during myelinogenesis. The basic dimensions of the myelin membrane are different. CNS myelin has a period repeat thickness of 15.7 nm whereas PNS myelin has a period to period line thickness of 18.5 nm, and the major dense line space is approximately 1.7 nm in CNS myelin, compared with 2.5 nm in PNS myelin. Myelin membrane contains protein, lipid and water, which forms at least 20% of the wet weight. It is a relatively lipid-rich membrane and contains 70–80% lipid. All classes of lipid have been found; perhaps not surpris - ingly, the precise lipid composition of PNS and CNS myelin is different. The major lipid species are cholesterol (the most common single mol - ecule), phospholipids and glycosphingolipids. Minor lipid species include galactosylglycerides, phosphoinositides and gangliosides. The major glycolipids are galactocerebroside and its sulphate ester, sul - phatide; these lipids are not unique to myelin but they are present in characteristically high concentrations. CNS and PNS myelin also contain low concentrations of acidic glycolipids, which constitute important antigens in some inflammatory demyelinating states. Gan - gliosides, which are glycosphingolipids characterized by the presence of sialic acid (N-acetylneuraminic acid), account for less than 1% of the lipid in myelin. A relatively small number of protein species account for the majority of myelin protein. Some of these proteins are common to both PNS and CNS myelin, but others are different. Proteolipid protein (PLP) and its splice variant DM20 are found only in CNS myelin, whereas myelin basic protein (MBP) and myelin associated glycoprotein (MAG) occur in both. MAG is a member of the immunoglobulin supergene family, and is localized specifically at those regions of the myelin segment where compaction starts: namely, the mesaxons and inner periaxonal membranes, paranodal loops and incisures, in both CNS and PNS sheaths. It is thought to have a functional role in membrane adhesion. In the developing CNS, axonal outgrowth precedes the migration of oligodendrocyte precursors, and oligodendrocytes associate with and myelinate axons after their phase of elongation; oligodendrocyte myelin gene expression is not dependent on axon association. In marked con - trast, Schwann cells in the developing PNS are associated with axons during the entire phase of axonal growth. Myelination does not occur simultaneously in all parts of the body in late fetal and early postnatal development. White matter tracts and nerves in the periphery have their own specific temporal patterns that relate to their degree of functional maturity. Mutations of the major myelin structural proteins have now been recognized in a number of inherited human neurological diseases. As would be expected, these mutations produce defects in myelination and in the stability of nodal and paranodal architecture that are consistent with the suggested functional roles of the relevant proteins in maintain - ing the integrity of the myelin sheath. EPENDYMA Ependymal cells line the ventricles ( Fig. 3.17; see Fig. 3.10) and central canal of the spinal cord. They form a single-layered epithelium that varies from squamous to columnar in form. At the ventricular surface, cells are joined by gap junctions and occasional desmosomes. Their apical surfaces have numerous microvilli and/or cilia, the latter contrib - uting to the flow of CSF. There is considerable regional variation in the Fig. 3.16 Suggested stages in myelination of a peripheral axon by an ensheathing Schwann cell. AxonInner mesaxonOuter mesaxonSchwann cell cytoplasmBasal lamina Fig. 3.17 Ciliated columnar epithelial lining of the lateral ventricle (V), overlying the subventricular zone (SVZ). C, cilia; E, ependymal cells. Mouse tissue, toluidine blue stained resin section. V C E SVZ

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Central glia 53 CHAPTER 3 MICROGLIA Microglia are the endogenous immune cells of the brain (Kettenmann et al 201 1, Eggen et al 2013). They originate from an embryonic mono - cyte precursor and invade the brain early during development. While the invading cells have an ameboid morphology, microglial cells in a mature brain are highly ramified cells. They have elongated nuclei, scant cytoplasm and several highly branched processes. They occupy a defined territory in the brain parenchyma and are found in all areas of the CNS including optic nerve, retina and spinal cord. Their density shows little variation. Resting microglia, a term used to refer to microglia in the normal brain, should more accurately be described as surveying microglia. Microglial processes are fast-moving structures that rapidly scan their territory while the soma remains fixed in position. Microglial cells express receptors for neurotransmitters and thus can sense neuronal activity. It is likely that they interact with synapses, from which it has been inferred that they may influence synaptic transmission. All pathological changes in the brain result in the activation of microglial cells (Fig. 3.19), e.g. activated microglia are found in the brain tissue of multiple sclerosis, Alzheimer’s disease and stroke patients. The most common indication of their activation is a change from a ramified to an ameboid morphology, which may occur within a few hours of the onset of injury or disease process. In general, microglia respond to two types of signal: ‘on’ signals, which either appear de novo or are strongly upregulated, e.g. cell wall compo - nents of invading bacteria; and ‘off’ signals, which are normally present but disappear or decrease in pathological states, e.g. defined cytokines or neurotransmitters. Both types of event are interpreted as signals for activation. The functional repertoire of activated microglia includes pro - liferation; migration to the site of injury; expression of major histocom - patibility complex (MHC) II molecules to interact with infiltrating lymphocytes; and the release of a variety of different substances including chemokines, cytokines and growth factors. These cells are therefore capa - ble of significantly influencing ongoing pathological processes. Microglial cells are the professional phagocytes of the nervous system and actively migrate through tissue. A number of factors such as ATP and complement factors act as chemoattractants. This behaviour is relevant not only in pathology but also during development where microglial cells remove apoptotic cells. After a pathological insult, microglial cells revert to their surveying phenotype, re-acquiring a rami - fied morphology. Entry of inflammatory cells into the brain Although the CNS has long been considered to be an immunologically privileged site, lymphocyte and macrophage surveillance of the brain may be a normal, but very low-grade, activity that is enhanced in disease. Lymphocytes can enter the brain in response to virus infections and as part of the autoimmune response in multiple sclerosis. Activated, but not resting, lymphocytes pass through the endothelium of small venules, a process that requires the expression of recognition and adhe - sion molecules (induced following cytokine activation), and subse-quently migrate into the brain parenchyma. Within the CNS, microglia can be induced by T-cell cytokines to act as efficient antigen-presenting cells. After leaving the CNS, lymphocytes probably drain along lym - phatic pathways to regional cervical lymph nodes.Choroid plexus The choroid plexus forms the CSF and actively regulates the concentra - tion of molecules in the CSF. It consists of highly vascularized masses of pia mater enclosed by pockets of ependymal cells. The ependymal cells resemble those of the circumventricular organs, except that they do not have basal processes, but form a cuboidal epithelium that rests on a basal lamina adjacent to the enclosed fold of meningeal pia mater and its capillaries (Fig. 3.18). The cells have numerous long microvilli with only a few cilia interspersed between them. They also have many mitochondria, large Golgi complexes and basal nuclei, features consist - ent with their secretory activity; they produce most components of the CSF. They are linked by tight junctions forming a transepithelial barrier (a component of the blood–CSF barrier), and by desmosomes. Their lateral margins are highly folded. The choroid plexus has a villous structure where the stroma is com- posed of pial meningeal cells, and contains fine bundles of collagen and blood vessels. Choroidal capillaries are lined by a fenestrated endothelium. During fetal life, erythropoiesis occurs in the stroma, which is occupied by bone marrow-like cells. In adult life, the stroma contains phagocytic cells, which, together with the cells of the choroid plexus epithelium, phagocytose particles and proteins from the ven - tricular lumen. Age-related changes occur in the choroid plexus, which can be detected by neuroimaging. Calcification of the choroid plexus can be detected by X-ray or CT scan very rarely in individuals in the first decade of life and in the majority in the eighth decade. The incidence of calci - fication rises sharply, from 35% of CT scans in the fifth decade to 75% in the sixth decade. Visible calcification is usually restricted to the glomus region of the choroid plexus, i.e. the vascular bulge in the choroid plexus as it curves to follow the anterior wall of the lateral ventricle into the temporal horn. Fig. 3.18 A, A choroid plexus within the lateral ventricle. Frond-like projections of vascular stroma derived from the pial meninges are covered with a low columnar epithelium that secretes cerebrospinal fluid. Mouse tissue, toluidine blue stained resin section. B, The arrangement of tissues forming the choroid plexus. Arachnoid materPia mater CNSSubarachnoid spaceChoroid fissureCapillary CNS VentricleChoroid epithelium Choroid capillary Ependyma A B Fig. 3.19 Activated microglial cells in the human central nervous system, in a biopsy from a patient with Rasmussen’s encephalitis, visualized using MHC class II antigen immunohistochemistry. (Courtesy of Dr Norman Gregson, Division of Neurology, GKT School of Medicine, London.)

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NERvOuS SySTEm 54 SECTION 1 fibres. B fibres are myelinated autonomic preganglionic efferent fibres. C fibres are unmyelinated and have thermoreceptive, nociceptive and interoceptive functions, including the perception of slow, burning pain and visceral pain. This scheme can be applied to fibres of both spinal and cranial nerves except perhaps those of the olfactory nerve, where the fibres form a uniquely small and slow group. The largest somatic efferent fibres (A α) innervate extrafusal muscle fibres (at motor end- plates) exclusively and conduct at a maximum of 120 m/s. Fibres to fast twitch muscles are larger than those to slow twitch muscle. Smaller (A γ) fibres of gamma motor neurones, and autonomic preganglionic (B) and postganglionic (C) efferent fibres conduct, in order, progressively more slowly (40 m/s to less than 10 m/s). A different classification, used for afferent fibres from muscles, divides fibres into groups I–IV on the basis of their calibre; groups I–III are myelinated and group IV is unmyelinated. Group I fibres are large (12–22 µm), and include primary sensory fibres of muscle spindles (group Ia) and smaller fibres of Golgi tendon organs (group Ib). Group II fibres are the secondary sensory terminals of muscle spindles, with diameters of 6–12 µm. Group III fibres, 1–6 µm in diameter, have free sensory endings in the connective tissue sheaths around and within muscles and are nociceptive and, in skin, also thermosensitive. Group IV fibres are unmyelinated, with diameters below 1.5 µm; they include free endings in skin and muscle, and are primarily nociceptive. CONNECTIVE TISSUE SHEATHS Nerve trunks, whether uni- or multifascicular, are limited externally by an epineurium, which is connected to surrounding tissues by mesoneu- rium. Mesoneurium is a loose connective tissue sheath (see Ch. 2) containing the extrinsic, segmental blood supply of the nerve, and so is of clinical importance in nerve injury. Individual fasciculi of the nerve trunk are enclosed by a multilayered perineurium, which in turn sur - rounds the endoneurium or intrafascicular connective tissue (see Fig. 3.20). Epineurium Epineurium is a condensation of loose (areolar) connective tissue derived from mesoderm. As a general rule, the more fasciculi present in a peripheral nerve, the thicker the epineurium. Epineurium contains fibroblasts, collagen (types I and III) and variable amounts of fat, and it cushions the nerve it surrounds. Loss of this protective layer may be associated with pressure palsies seen in wasted, bedridden patients. The epineurium also contains lymphatics (which probably pass to regional lymph nodes) and blood vessels, vasa nervorum, that pass across the perineurium to communicate with a network of fine vessels within the endoneurium, forming the intrinsic system of vascular plexuses. Perineurium Perineurium extends from the CNS–PNS transition zone to the periph - ery, where it is continuous with the capsules of muscle spindles and encapsulated sensory endings, but ends openly at unencapsulated endings and neuromuscular junctions. It consists of alternating layers of flattened polygonal cells (thought to be derived from fibroblasts) and collagen. It can often contain 15–20 layers of such cells, each layer enclosed by a basal lamina up to 0.5 µm thick. Within each layer the cells interdigitate along extensive tight junctions; their cytoplasm typi - cally contains vesicles and bundles of microfilaments and their plasma membrane often shows evidence of pinocytosis. These features are con - sistent with the function of the perineurium as a metabolically active diffusion barrier; together with the blood–nerve barrier, the perineu - rium is thought to play an essential role in maintaining the osmotic milieu and fluid pressure within the endoneurium. Lymphatic vessels have not been detected in the perineurium. Endoneurium Strictly speaking, the term endoneurium is restricted to intrafascicular connective tissue and excludes the perineurial partitions within fasci - cles. Endoneurium consists of a fibrous matrix composed predomi - nantly of type III collagen (reticulin) fibres, characteristically organized in fine bundles lying parallel to the long axis of the nerve, and con - densed around individual Schwann cell–axon units and endoneurial vessels. The fibrous and cellular components of the endoneurium are bathed in endoneurial fluid at a slightly higher pressure than that outside in the surrounding epineurium. The major cellular constituents Monocytes enter the CNS in the early stages of infarction and autoimmune disease and, in particular, in pyogenic infections, probably by passing through the endothelium of local vessels. Once in the brain, monocytes are difficult to distinguish from intrinsic microglia because both cell types express a similar marker profile. During the inflamma - tory phase of meningitis, polymorphonuclear leukocytes and lym - phocytes pass into the CSF through the endothelium of large veins in the subarachnoid space. Recent developments in research on brain inflammatory disorders are reviewed in Anthony and Pitossi (2013). PERIPHERAL NERVES Afferent nerve fibres connect peripheral receptors to the CNS; they are derived from neuronal somata located either in special sense organs (e.g. the olfactory epithelium) or in the sensory ganglia of the cranio - spinal nerves. Efferent nerve fibres connect the CNS to the effector cells and tissues and are the peripheral axons of neurones with somata in the central grey matter. Peripheral nerve fibres are grouped in widely variable numbers into bundles (fasciculi). The size, number and pattern of fasciculi vary in different nerves and at different levels along their paths ( Fig. 3.20). Their number increases and their size decreases some distance proximal to a point of branching. Where nerves are subjected to pressure, e.g. deep to a retinaculum, fasciculi are increased in number but reduced in size, and the amount of associated connective tissue and degree of vascularity also increase. At these points, nerves may occasionally show a pink, fusiform dilation, sometimes termed a pseudoganglion or gan- gliform enlargement. CLASSIFICATION OF PERIPHERAL NERVE FIBRES Classification of peripheral nerve fibres is based on various parameters such as conduction velocity, function and fibre diameter. Of two clas - sifications in common use, the first divides fibres into three major classes, designated A, B and C, corresponding to peaks in the distribu - tion of their conduction velocities. In humans, this classification is used mainly for afferent fibres from the skin. Group A fibres are subdivided into α, β, γ and δ subgroups; fibre diameter and conduction velocity are proportional in most fibres. Group A α fibres are the largest and conduct most rapidly, and C fibres are the smallest and slowest. The largest afferent axons (A α fibres) innervate encapsulated cutane - ous mechanoreceptors, Golgi tendon organs and muscle spindles, and some large alimentary enteroceptors. Aβ fibres form secondary endings on some muscle spindle (intrafusal) fibres and also innervate cutaneous and joint capsule mechanoreceptors. Aδ fibres innervate thermorecep- tors, stretch-sensitive free endings, hair receptors and nociceptors, including those in dental pulp, skin and connective tissue. A γ fibres are exclusively fusimotor to plate and trail endings on intrafusal muscle Fig. 3.20 A transverse section of a biopsied human sural nerve, showing the arrangement of the connective tissue sheaths. Individual axons, myelinated and unmyelinated, are arranged in a small fascicle bounded by a perineurium. Abbreviations: P, perineurium; Ep, epineurium; E, endoneurium. (Courtesy of Professor Susan Standring, GKT School of Medicine, London.) EP Ep

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Peripheral nerves 55 CHAPTER 3 et al 2008). The region under the compact myelin sheath that extends between two juxtaparanodes is the internode. The molecular domains of myelinated axons, including that of the axon initial segment are reviewed in Buttermore et al (2013)). Schwann cell cytoplasm forms a continuous layer only in the peri - nuclear (mid-internodal) and paranodal regions, where it forms a collar from which microvilli project into the nodal gap substance. Elsewhere it is dispersed as a lace-like network over the inner (adaxonal) and outer (abaxonal) surfaces of the myelin sheath. Nodes of Ranvier The nodal compartment consists of a short length of exposed axo - lemma, typically 0.8–1.1 µm long, surrounded by a nodal gap sub - stance composed of various extracellular components, some of which may possess nerve growth-repulsive characteristics. Multiple processes (microvilli) protrude into the gap substance from the outer collar of Schwann cytoplasm and contact the nodal axolemma. Voltage-gated Na + channels, the cell adhesion molecules NrCAM and neurofascin-186, the cytoskeletal adaptor ankyrin G25,26 and the actin-binding protein spectrin βIV are clustered at nodes. The calibre of the nodal axon is usually significantly less than that of the internodal axon, particularly in large-calibre fibres. Paranodes The axolemma on either side of a node is contacted by paranodal loops of Schwann cell cytoplasm via specialized septate junctions that spiral around the axon. The junctions are thought to form a partial diffusion barrier into the peri-axonal space; restrict the movement of K+ channels from under the compact myelin; and limit lateral diffusion of mem - brane components. Caspr, contactin and their putative ligand NF155 (an isoform of neurofascin) are concentrated in paranodes. Juxtaparanodes The region of the axon lying just beyond the innermost paranodal junc - tion is now recognized as a distinct domain defined by the localization of voltage-gated K+ channels (delayed-rectifier K+ channels Kv1.1, Kv1.2 and their Kvb2 subunit). Clustering of Kv1 channels at the juxtapara - nodal region depends on their association with the Caspr2/TAG-1 adhe - sion complex. Schmidt–Lanterman incisures Schmidt–Lanterman incisures are helical decompactions of internodal myelin that appear as funnel-like profiles in teased fibre preparations labelled for markers of non-compacted myelin (e.g. MAG, Cx32). At an incisure the major dense line of the myelin sheath splits to enclose a continuous spiral band of cytoplasm passing between abaxonal and adaxonal layers of Schwann cell cytoplasm. The minor dense line of incisural myelin is also split, creating a channel connecting the peri-axonal space with the endoneurial extracellular fluid. The function of of the endoneurium are Schwann cells and endothelial cells; minor components are fibroblasts (constituting approximately 4% of the total endoneurial cell population), resident macrophages and mast cells. Schwann cell–axon units and blood vessels are enclosed within indi - vidual basal laminae and therefore isolated from the other cellular and extracellular components of the endoneurium. Endoneurial arterioles have a poorly developed smooth muscle layer and do not autoregulate well. In sharp contrast, epineurial and perineu - rial vessels have a dense perivascular plexus of peptidergic, serotonin - ergic and adrenergic nerves. There are free nerve endings in all layers of neural connective tissue sheaths and there are some encapsulated (Pacinian) corpuscles in the endoneurium. These probably contribute to the acute sensitivity of nerves trapped in fibrosis after injury or surgery. SCHWANN CELLS Schwann cells are the major glial type in the PNS. In vitro they are fusiform in appearance. Both in vitro and in vivo, Schwann cells ensheathe peripheral axons, and myelinate those greater than 2 µm in diameter. In a mature peripheral nerve, they are distributed along the axons in longitudinal chains; the geometry of their association depends on whether the axon is myelinated or unmyelinated. In myelinated axons the territory of a Schwann cell defines an internode. The molecular phenotype of mature myelin-forming Schwann cells is different from that of mature non-myelin-forming Schwann cells. Adult myelin-forming Schwann cells are characterized by the presence of several myelin proteins, some, but not all, of which are shared with oligodendrocytes and central myelin. In contrast, expression of the low-affinity neurotrophin receptor (p75NTR) and GFAP intermediate filament protein (which differs from the CNS form in its post-translational modification) characterizes adult non-myelin-forming Schwann cells. Schwann cells arise from Schwann cell precursors that, in turn, are generated from multipotent cells of the neural crest. Neuronal signals regulate many aspects of Schwann cell behaviour in developing and postnatal nerves. Axon-associated signals appear to control the prolif - eration of developing Schwann cells and their precursors; the develop - mentally programmed death of those precursors in order to match numbers of axons and glia within each peripheral nerve bundle; the production of basal laminae by Schwann cells; and the induction and maintenance of myelination. Axonal neuregulin 1 signalling via ErbB2/ B3 receptors on Schwann cells is essential for Schwann cell myelination and also determines myelin thickness. An extensive literature supports the view that Schwann cells are key players in the acute injury response in the PNS (see Commentary 1.6 ), helping to provide a microenviron - ment that facilitates axonal regrowth (Birch 201 1). Few Schwann cells persist in chronically denervated nerves. For further reading about Schwann cells, see Kidd et al (2013). Unmyelinated axons Unmyelinated axons are commonly 1.0 µm in diameter, although some may be 1.5 µm or even 2 µm in diameter. Groups of up to 10 or more small axons (0.15–2.0 µm in diameter) are enclosed within a chain of overlapping Schwann cells that is surrounded by a basal lamina. Within each Schwann cell, individual axons are usually sequestered from their neighbours by delicate processes of cytoplasm. It seems likely, on the basis of quantitative studies in subhuman primates, that axons from adjacent cord segments may share Schwann cell columns; this phenom - enon may play a role in the evolution of neuropathic pain after nerve injury. In the absence of a myelin sheath and nodes of Ranvier, action potential propagation along unmyelinated axons is not saltatory but continuous, and relatively slow (0.5–4.0 m/s). Myelinated axons Myelinated axons (Fig. 3.21 ) have a 1 : 1 relationship with their ensheathing Schwann cells. The territorial extent of individual Schwann cells varies directly with the diameter of the axon they surround, from 150 to 1500 µm. Specialized domains of axo-glial interaction define nodes of Ranvier and their neighbouring compartments, paranodes and juxtaparanodes (Pereira et al 2012; Fig. 3.22). These domains contain multiprotein complexes characterized by unique sets of transmembrane and cytoskeletal proteins and clusters of ion channels; the mechanisms regulating channel clustering and node formation remain a subject of intense scrutiny (Peles and Salzer 2000, Poliak and Peles 2003, Horresh Fig. 3.21 An electron micrograph of a transverse section of biopsied human sural nerve, showing a myelinated axon and several unmyelinated axons (A), ensheathed by Schwann cells (S). (Courtesy of Professor Susan Standring, GKT School of Medicine, London.) S SA A A

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NERvOuS SySTEm 56 SECTION 1 from horizontal basal stem cells in the olfactory epithelium (Leung et al 2007, Forni and Wray 2012). They extend new axons through the lamina propria and cribriform plate into the CNS environment of the olfactory bulb, where they synapse with second-order neurones. Olfac - tory ensheathing cells (OECs, also known as olfactory ensheathing glia) accompany olfactory axons from the lamina propria of the olfactory epithelium to their synaptic contacts in the glomeruli of the olfactory bulbs and are thought to play a role in directing them to their correct position in the olfactory bulb (Higginson and Barnett 201 1). This unusual arrangement is unique; elsewhere in the nervous system the territories of peripheral and central glia are clearly demarcated at CNS– PNS transition zones. OECs and the end-feet of astrocytes lying between the bundles of olfactory axons both contribute to the glia limitans at the pial surface of the olfactory bulbs. OECs share many properties with Schwann cells and express similar antigenic and morphological properties. They ensheathe olfactory sensory axons in a manner comparable to the relationship that exists transitorily between Schwann cells and axons in very immature periph - eral nerves, i.e. they surround, but do not segregate, bundles of up to 50 fine unmyelinated axons to form approximately 20 fila olfactoria. Both OECs and Schwann cells can myelinate axons, even though nor - mally none of the axons in the olfactory nerve is myelinated. It was thought that OECs shared a common origin with olfactory receptor neurones in the olfactory placode, but recent fate-mapping experiments in chicken embryos and genetic linkage-tracing studies in mice have shown that OECs are derived from neural crest cells (Forni and Wray 2012). OECs have a malleable phenotype. There may be several subtypes: some OECs express GFAP as either fine filaments or more diffusely in their cytoplasm, and some express p75 NTR and the O4 antigen.incisures is not known; their structure suggests that they may participate in transport of molecules across the myelin sheath. SATELLITE CELLS Many non-neuronal cells of the nervous system have been called satel - lite cells, including small, round extracapsular cells in peripheral ganglia, ganglionic capsular cells, Schwann cells, any cell that is closely associated with neuronal somata, and precursor cells associated with striated muscle fibres (Hanani 2010). Within the nervous system, the term is most commonly reserved for flat, epithelioid cells (ganglionic glial cells, capsular cells) that surround the neuronal somata of periph - eral ganglia (see Fig. 3.23). Their cytoplasm resembles that of Schwann cells, and their deep surfaces interdigitate with reciprocal infoldings in the membranes of the enclosed neurones. Enteric glia Enteric nerves lack an endoneurium and so do not have the collagenous coats of other peripheral nerves. The enteric ganglionic neurones are supported by glia that closely resemble astrocytes; they contain more GFAP than non-myelinating Schwann cells and do not produce a basal lamina. Evidence for their roles in gut function is reviewed in Gul- bransen and Sharkey (2012). Olfactory ensheathing glia The olfactory system is unusual because it supports neurogenesis throughout life. Olfactory receptor neurones are continuously renewed Fig. 3.22 The general plan of a peripheral myelinated nerve fibre in longitudinal section, including one complete internodal segment and two adjacent paranodal bulbs, used as a key for the more detailed microarchitecture of specific subregions. A, A transverse electron microscope section through the centre of a node of Ranvier, with numerous finger-like processes of adjacent Schwann cells converging towards the nodal axolemma. Many microtubules and neurofilaments are visible within the axoplasm. B, The arrangement of the axon, myelin sheath and Schwann cell cytoplasm at the node of Ranvier, in the paranodal bulbs and in the juxtaparanodal region. The axon is myelinated by a Schwann cell surrounded by a basal lamina (BL). Only a portion of the internode, which is located beneath the compact myelin (CM) sheath, is shown. A spiral of paranodal (green) and juxtaparanodal (blue) proteins extends into the internode; this spiral is apposed to the inner mesaxon of the myelin sheath (not shown). K + channels and Caspr2 are concentrated in the juxtaparanodal region. In the paranodal region, the compact myelin sheath opens up into a series of paranodal cytoplasmic loops (PNL) that invaginate and closely appose the axon, forming a series of septum-like junctions that spiral around the axon. Caspr, contactin and an isoform of neurofascin (NF155) are concentrated in this region. At the node, numerous microvilli (MV) project from the outer collar of the Schwann cell to contact the axolemma. The axon is enormously enriched in intramembranous particles at the node that correspond to Na+ channels (Na+ ch). Ankyrin G (ank G) isoforms and the cell adhesion molecules NrCAM and NF186 are also concentrated in this region. (A, Courtesy of Professor Susan Standring, GKT School of Medicine, London. B, Redrawn from Peles and Salzer 2000.) MV Internode Juxtaparanode • Caspr 2• Kv1.1, 1.2, β2Paranode• Caspr• Contactin• NF155Node• Na + ch • ank G• NrCAM• NF186PNL PNL PNLCM CM EPBLB A

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Peripheral nerves 57 CHAPTER 3 processes; in myelinated fibres the junction occurs at a node of Ranvier. The peripheral process terminates in a sensory ending and, because it conducts impulses towards the soma, it functions as an elongated den - drite, strictly speaking. However, it has the typical structural and func - tional properties of a peripheral axon, and is conventionally described as an axon. Each neuronal soma is surrounded by a sheath of satellite glial cells (SGCs). (A notable exception is the spiral, or cochlear, ganglion, where most neuronal somata are myelinated, presumably contributing to fast electrical transmission.) The axodendritic process and its peripheral and central divisions, ensheathed by Schwann cells, lie outside the SGC sheath. All the cells in the ganglion lie within a highly vascularized connective tissue that is continuous with the endoneurium of the nerve root. In dorsal root ganglia there is no clear regional mapping of the innervated body regions. In contrast, each of the three nerve branches (ophthalmic, maxillary and mandibular) of the trigeminal nerve is mapped to a different part of the trigeminal ganglion. Although sensory neurones receive no synapses, they are endowed with receptors for numerous neurotransmitters and hormones, and can thus communi - cate chemically amongst themselves and with SGCs. SGCs are the main type of glial cell in sensory ganglia. They share several properties with astrocytes, including expression of glutamine synthetase and various neurotransmitter transporters. In addition, like astrocytes, the SGCs that surround a neurone are coupled by gap junc - tions and express receptors for ATP. Unlike astrocytes, SGCs completely surround individual sensory neurones (and more rarely two or three neurons) in a glial sheath. They undergo major changes as a result of injury to peripheral nerves, and appear to contribute to chronic pain in a number of animal pain models. Herpes zoster Primary infection with the varicella zoster virus causes chickenpox. Following recovery, the virus remains dormant within dorsal root ganglia or trigeminal ganglia, mostly in the neurones, and less commonly in the SGCs. Reactivation of the virus leads to herpes zoster (shingles), which involves the dermatome(s) supplied by the affected sensory nerve(s). Diagnostic signs are severe pain, erythema and blistering as occurs in chickenpox, often confined to one of the divisions of the trigeminal nerve or to a spinal nerve dermatome. Herpes zoster involving the geniculate ganglion compresses the facial nerve and results in a lower motor neurone facial paralysis, known as Ramsay Hunt syndrome. Occasionally, if the vestibulocochlear nerve becomes involved, there is vertigo, tinnitus and some deafness. The most important complication of herpes zoster is post-herpetic neural - gia, a severe and persistent pain that is highly refractory to treatment. Autonomic ganglia The main types of cell in autonomic ganglia are the ganglionic neu - rones, small intensely fluorescent (SIF) cells and satellite glial cells (SGCs). Most of the neurones have somata ranging from 25 to 50 µm and complex dendritic fields; dendritic glomeruli have been observed in ganglia in experimental animals. Ganglionic neurones receive many axodendritic synapses from preganglionic axons; axosomatic synapses are less numerous. Postganglionic fibres commonly arise from the initial stem of a large dendrite and produce few or no collateral proc - esses. Given their close relationship to the ganglionic neurones, auto - nomic SGCs may have the potential to influence synaptic transmission. SIF cells are characterized by being smaller than the neurones and by having numerous granules that contain noradrenaline (norepine- phrine), dopamine and serotonin. They are almost completely invested by a sheath of SGCs and receive and make synapses; their physiological role is currently obscure, but they lend credence to the idea that auto - nomic ganglia are far more than simple relay stations. Sympathetic neurones are multipolar and their dendritic trees, on which preganglionic motor axons synapse, are more elaborate than those of parasympathetic neurones (Fig. 3.24). The neurones are sur- rounded by a mixed neuropil of afferent and efferent fibres, dendrites, synapses and non-neural cells. There is considerable variation in the ratio of pre- and postganglionic fibres in different types of ganglion. Preganglionic sympathetic axons may synapse with many postgangli - onic neurones for the wide dissemination and perhaps amplification of sympathetic activity, a feature not found to the same degree in para - sympathetic ganglia. Dissemination may also be achieved by connec - tions with ganglionic interneurones or by the diffusion within the ganglion of transmitter substances produced either locally (paracrine effect) or elsewhere (endocrine effect). Some axons within a ganglion may be efferent fibres en route to another ganglion, or afferents from viscera and glands. These fibres may synapse with neurones in the BLOOD SUPPLY OF PERIPHERAL NERVES The blood vessels supplying a nerve, end in a capillary plexus that pierces the perineurium. The branches of the plexus run parallel with the fibres, connected by short transverse vessels, forming narrow, rec - tangular meshes similar to those found in muscle. The blood supply of peripheral nerves is unusual. Endoneurial capillaries have atypically large diameters and intercapillary distances are greater than in many other tissues. Peripheral nerves have two separate, functionally inde - pendent vascular systems: an extrinsic system (regional nutritive vessels and epineurial vessels) and an intrinsic system (longitudinally running microvessels in the endoneurium). Anastomoses between the two systems produce considerable overlap between the territories of the segmental arteries. This unique pattern of vessels, together with a high basal nerve blood flow relative to metabolic requirements, means that peripheral nerves possess a high degree of resistance to ischaemia. Blood–nerve barrier Just as the neuropil within the CNS is protected by a blood–brain barrier, the endoneurial contents of peripheral nerve fibres are protected by a blood–nerve barrier and by the cells of the perineurium. The blood–nerve barrier operates at the level of the endoneurial capillary walls, where the endothelial cells are joined by tight junctions, and are non-fenestrated and surrounded by continuous basal laminae. The barrier is much less efficient in dorsal root ganglia and autonomic ganglia and in the distal parts of peripheral nerves. GANGLIA Ganglia are aggregations of neuronal somata and are of varying form and size. They occur in the dorsal roots of spinal nerves; in the sensory roots of the trigeminal, facial, vestibulocochlear, glossopharyngeal and vagal cranial nerves; and in the peripheral autonomic nervous system (ANS). Each ganglion is enclosed within a capsule of fibrous connective tissue and contains neuronal somata and neuronal processes. Enteric ganglia are an exception to this rule; they resemble the CNS in both structure and function, and are not covered by a connective tissue capsule. Some ganglia, particularly in the ANS, contain axons that originate from neuronal somata that lie elsewhere in the nervous system and which pass through the ganglia without synapsing. Sensory ganglia The sensory ganglia of dorsal spinal roots (Fig. 3.23) and the ganglia of the trigeminal, facial, glossopharyngeal and vagal cranial nerves are enclosed in a periganglionic connective tissue capsule that resembles the perineurium surrounding peripheral nerves. Ganglionic neurones are unipolar (sometimes called pseudounipolar, see above). They have spherical or oval somata of varying size, aggregated in groups between fasciculi of myelinated and unmyelinated nerve fibres. For each neurone, a single axodendritic process bifurcates into central and peripheral Fig. 3.23 Sensory neurones in a dorsal root ganglion (rat). Neurones (N) are typically variable in size but all are encapsulated by satellite cells (S). Myelinated axons are seen above and below the neuronal somata. Toluidine blue stained resin section. (Courtesy of Dr Clare Farmer, King’s College, London.) N SS

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NERvOuS SySTEm 58 SECTION 1 the neonatal period. Treatment usually consists of removing the dis - eased intestinal segment. The enteric plexuses consist of sensory neurones, interneurones and a variety of motor neurones. These neurones are endowed with recep - tors for a large number of neurotransmitters and also release a variety of neurotransmitters. All classes of enteric neurone are equally distrib - uted along the entire ganglionic network; consequently the ENS con - sists of numerous repeating modules. The myenteric plexus contains the motor neurones that control the movements of gastrointestinal smooth muscle. The main excitatory neurotransmitter is acetylcholine, which may be co-localized with an excitatory peptide (usually a tachykinin, such as substance P). The main inhibitory neurotransmitter is nitric oxide (NO), released from neu- rones that may also release the inhibitory peptide vasoactive intestinal peptide (VIP). An important function of myenteric neurones is to mediate the peri - staltic reflex, which is induced by intestinal wall distension or by mechanical stimulation of the mucosa. These stimuli initiate contrac - tion oral to the site of the stimulus, and relaxation anal to the site, creat - ing a pressure gradient that propels the intestinal contents. Interstitial cells of Cajal (ICC) are pacemaker cells believed to integrate neuronal signals with rhythmic oscillations of muscle contraction; disturbance of ICC function may be a factor in a number of gastrointestinal disorders (Huizinga et al 2009). Enteric glia are the main type of glial cell in the ENS. In some respects they resemble astrocytes, e.g. they form end-feet with blood vessels, respond to numerous chemical mediators, and are extensively coupled among themselves by gap junctions. They appear to play an important role in neuroprotection and in maintaining the integrity of the intestinal mucosal barrier. DISPERSED NEUROENDOCRINE SYSTEM Although the nervous, neuroendocrine and endocrine systems all operate by intercellular communication, they differ in the mode, speed and degree or localization of the effects produced (Day and Salzet 2002). The autonomic nervous system uses impulse conduction and neurotransmitter release to transmit information, and the responses induced are rapid and localized. The dispersed neuroendocrine system uses only secretion. It is slower and the induced responses are less local - ized, because the secretions, e.g. neuromediators, can act either on contiguous cells, or on groups of nearby cells reached by diffusion, or on distant cells via the blood stream. Many of its effector molecules operate in both the nervous system and the neuroendocrine system. The endocrine system proper, which consists of clusters of cells and discrete, ductless, hormone-producing glands, is even slower and less localized, although its effects are specific and often prolonged. These regulatory systems overlap in function, and can be considered as a single neuroendocrine regulator of the metabolic activities and internal environment of the organism, acting to provide conditions in which it can function successfully. Neural and neuroendocrine axes appear to cooperate to modulate some forms of immunological reaction; the extensive system of vessels, circulating hormones and nerve fibres that link the brain with all viscera are thought to constitute a neuroimmune network (Fig. 3.26). Some cells can take up and decarboxylate amine precursor com - pounds (amine precursor uptake and decarboxylation, or APUD, cells). They are characterized by dense-core cytoplasmic granules (see Fig. 2.6), similar to the neurotransmitter vesicles seen in some types of neuronal terminal. The group includes cells described as chromaffin cells (phaeo - chromocytes), derived from neuroectoderm and innervated by pregan - glionic sympathetic nerve fibres. Chromaffin cells synthesize and secrete catecholamines (dopamine, noradrenaline (norepinephrine) or adren - aline (epinephrine)). Their name refers to the finding that their cyto - plasmic store of catecholamines is sufficiently concentrated to give an intense yellow–brown colouration, the positive chromaffin reaction, when they are treated with aqueous solutions of chromium salts, par - ticularly potassium dichromate. Classic chromaffin cells include clus-ters of cells in the suprarenal medulla; the para-aortic bodies, which secrete noradrenaline; paraganglia; certain cells in the carotid bodies; and small groups of cells irregularly dispersed among the paravertebral sympathetic ganglia, splanchnic nerves and prevertebral autonomic plexuses. The alimentary tract contains a large population of cells of a similar type (previously called neuroendocrine or enterochromaffin cells) in its wall. These cells act as sensory transducers, activating intrinsic and extrinsic primary afferent neurones via their release of 5- hydroxytryptamine (5-HT, serotonin). The neonatal respiratory tract ganglion, e.g. substance P-containing axons of dorsal root neurones synapse on neurones in prevertebral ganglia, thereby enabling interac - tions between the sensory system and the ANS. Enteric ganglia The enteric nervous system (ENS) lies within the walls of the gastroin-testinal tract (see Fig. 2.15 for the layers of a typical viscus) and includes the myenteric and submucosal plexuses and associated ganglia (Furness 2012, Neunlist et al 2013). The ganglionic neurones ( Fig. 3.25) serve different functions, including the regulation of gut motility (in conjunc - tion with interstitial cells of Cajal (Huizinga et al 2009)), mucosal transport and mucosal blood flow. Unlike the other two divisions of the ANS, the ENS is largely independent of the CNS, and the extrinsic autonomic fibres that supply the gut wall exert only modulatory effects on it. Submucosal neurones, together with sympathetic axons, regulate the local blood flow. Hirschsprung’s disease is a congenital disease in which dysfunctional neural crest migration means that the ganglia of both the myenteric and submucosal plexuses in the distal bowel fail to develop. The resulting lack of propulsive activity in the aganglionic bowel leads to functional obstruction and megacolon, which can be life-threatening. Around 1 in 5,000 infants is born with the condition and is typically diagnosed in Fig. 3.24 A parasympathetic autonomic ganglion from a human stomach. Large neuronal somata, some with nuclei and prominent nucleoli in the plane of section, are encapsulated by satellite cells and surrounded by nerve fibres and non-neuronal cells. (Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.) Fig. 3.25 An enteric ganglion (outlined) of the myenteric (Auerbach’s) plexus between the inner circular and outer longitudinal layers of smooth muscle (M) in the wall of the human intestine. An enteric ganglionic neurone is arrowed. (Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.) MM

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Sensory endings 59 CHAPTER 3 receptor and partly in the neurone that innervates it, in the case of epithelial receptors. Transduction varies with the modality of the stimu - lus, and usually causes depolarization of the receptor membrane (or hyperpolarization, in the retina). In mechanoreceptors, transduction may involve the deformation of membrane structure, which causes either strain or stretch-sensitive ion channels to open. In chemorecep - tors, receptor action may resemble that for ACh at neuromuscular junctions. Visual receptors share similarities with chemoreceptors: light causes changes in receptor proteins, which activate G proteins, resulting in the release of second messengers and altered membrane permeability. The quantitative responses of sensory endings to stimuli vary greatly and increase the flexibility of the functional design of sensory systems. Although increased excitation with increasing stimulus level is a common pattern (‘on’ response), some receptors respond to decreased stimulation (‘off’ response). Even unstimulated receptors show varying degrees of spontaneous background activity against which an increase or decrease in activity occurs with changing levels of stimulus. In all receptors studied, when stimulation is maintained at a steady level, there is an initial burst (the dynamic phase) followed by a gradual adaptation to steady level (the static phase). Though all receptors show these two phases, one or other may predominate, providing a distinc - tion between rapidly adapting endings that accurately record the rate of stimulus onset, and slowly adapting endings that signal the constant amplitude of a stimulus, e.g. position sense. Dynamic and static phases are reflected in the amplitude and duration of the receptor potential and also in the frequency of action potentials in the sensory fibres. The stimulus strength necessary to elicit a response in a receptor, i.e. its threshold level, varies greatly between receptors, and provides an extra level of information about stimulus strength. For further information on sensory receptors, see Nolte (2008). FUNCTIONAL CLASSIFICATION OF RECEPTORS Receptors have been classified in several ways. They may be classified by the modalities to which they are sensitive, such as mechanoreceptors (which are responsive to deformation, e.g. touch, pressure, sound waves, etc.), chemoreceptors, photoreceptors and thermoreceptors. Some re - ceptors are polymodal, i.e. they respond selectively to more than one modality; they usually have high thresholds and respond to damaging stimuli associated with irritation or pain (nociceptors). Another widely used classification divides receptors on the basis of their distribution in the body into exteroceptors, proprioceptors and interoceptors. Exteroceptors and proprioceptors are receptors of the somatic afferent components of the nervous system, while interoceptors are receptors of the visceral afferent pathways. Exteroceptors respond to external stimuli and are found at, or close to, body surfaces. They can be subdivided into the general or cutaneous sense organs and special sensory organs. General sensory receptors include free and encapsulated terminals in skin and near hairs; none of these has absolute specificity for a particular sensory modality. Special sensory organs are the olfactory, visual, acoustic, vestibular and taste receptors. Proprioceptors respond to stimuli to deeper tissues, especially of the locomotor system, and are concerned with detecting movement, mechanical stresses and position. They include Golgi tendon organs, muscle spindles, Pacinian corpuscles, other endings in joints, and ves - tibular receptors. Proprioceptors are stimulated by the contraction of muscles, movements of joints and changes in the position of the body. They are essential for the coordination of muscles, the grading of mus - cular contraction, and the maintenance of equilibrium. Interoceptors are found in the walls of the viscera, glands and vessels, where their terminations include free nerve endings, encapsulated ter - minals and endings associated with specialized epithelial cells. Nerve terminals are found in the layers of visceral walls and the adventitia of blood vessels, but the detailed structure and function of many of these endings are not well established. Encapsulated (lamellated) endings occur in the heart, adventitia and mesenteries. Free terminal arboriza - tions occur in the endocardium, the endomysium of all muscles, and connective tissue generally. Tension produced by excessive muscular contraction or by visceral distension often causes pain, particularly in pathological states, which is frequently poorly localized and of a deep-seated nature. Visceral pain is often referred to the corresponding der - matome (see Fig. 16.10). Polymodal nociceptors (irritant receptors) respond to a variety of stimuli such as noxious chemicals or damaging mechanical stimuli. They are mainly the free endings of fine, unmyeli - nated fibres that are widely distributed in the epithelia of the alimentary and respiratory tracts; they may initiate protective reflexes.contains a prominent system of neuroendocrine cells, both dispersed and aggregated (neuroepithelial bodies); the numbers of both types decline during childhood. Merkel cells (see Commentary 1.3 ) in the basal epidermis of the skin store neuropeptides, which they release to associated nerve endings or other cells in a neuroendocrine role, in response to pressure and possibly other stimuli (Lucarz and Brand 2007). Experimental animal studies have revealed 5-HT-containing intraepithelial paraneurones in the urothelial lining of the urethra; these cells are thought to relay information from the luminal surface of the urethra to underlying sensory nerves. A number of descriptions and terms have been applied to cells of this system in the older literature (see online text for details). For further reading, see Day and Salzet (2002). SENSORY ENDINGS GENERAL FEATURES OF SENSORY RECEPTORS There are three major forms of sensory receptor: neuroepithelial, epi - thelial and neuronal ( Fig. 3.27). A neuroepithelial receptor is a neurone with a soma lying near a sensory surface and an axon that conveys sensory signals into the CNS to synapse on second-order neurones. This is an evolutionarily primi - tive arrangement, and the only examples remaining in humans are the sensory neurones of the olfactory epithelium. An epithelial receptor is a cell that is modified from a non-nervous sensory epithelium and innervated by a primary sensory neurone with a soma lying near the CNS, e.g. auditory receptors and taste buds. When activated, this type of receptor excites its neurone by neurotransmission across a synaptic gap. A neuronal receptor is a primary sensory neurone that has a soma in a craniospinal ganglion and a peripheral axon ending in a sensory terminal. All cutaneous sensors and proprioceptors are of this type; their sensory terminals may be encapsulated or linked to special meso - dermal or ectodermal structures to form a part of the sensory apparatus. The extraneural cells are not necessarily excitable, but create an appro - priate environment for the excitation of the neuronal process. The receptor stimulus is transduced into a graded change of electrical potential at the receptor surface (receptor potential), and this initiates an all-or-none action potential that is transmitted to the CNS. This may occur either in the receptor, when this is a neurone, or partly in the Fig. 3.26 The ways in which the nervous system, neuroendocrine system and immune system are integrated, demonstrated in the intestine. Neurocrine signals from enteric neuroendocrine cells and signals from immune defence cells (e.g. lymphocytes, macrophages and mast cells) act on other cells of those systems and on neurones with sensory endings in the intestinal wall, either locally or at a distance. Some neuronal soma lie within enteric ganglia in the gut wall; others have their bodies in peripheral ganglia. Neuronal signals may act locally, be transmitted to the CNS or enter a reflex pathway via sympathetic ganglia. Gut lumenImmune and tissue defence signals:local and systemicIntestinofugal neurone Neurocrine signals:local and circulatingSpinal cordSpinal sensory neuronePrevertebral sympathetic ganglion Intrinsic sensory neurone StretchBrainstem Sensory vagal neurone Signals from lumen e.g. nutrients, antigens, irritants, secretions

Gray's Anatomy: 41st Edition

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Nervous system 59.e1 CHAPTER 3 They include: clear cells (so named because of their poor staining properties in routine preparations); argentaffin cells (reduce silver salts); argyrophil cells (absorb silver); small intensely fluorescent cells; peptide-producing cells (particularly of the hypothalamus, hypophysis, pineal and parathyroid glands, and placenta); Kulchitsky cells in the lungs; and paraneurones. Many cells of the dispersed (or diffuse) neu- roendocrine system are derived embryologically from the neural crest. Some – in particular, cells from the gastrointestinal system – are now known to be endodermal in origin.

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NERvOuS SySTEm 60 SECTION 1 Special types of free ending are associated with epidermal structures in the skin. They include terminals associated with hair follicles (peri - trichial receptors), which branch from myelinated fibres in the deep dermal cutaneous plexus; the number, size and form of the endings are related to the size and type of hair follicle innervated. These endings respond mainly to movement when hair is deformed and belong to the rapidly adapting mechanoreceptor group. Merkel tactile endings (see Commentary 1.3) lie either at the base of the epidermis or around the apical ends of some hair follicles, and most are innervated by large myelinated axons. Each axon expands into a disc that is applied closely to the base of a Merkel cell in the basal layer of the epidermis. The cells are believed to be derived from the epidermis, although a neural crest origin remains possible. They contain many large (50–100 nm) dense-core vesicles, presumably containing transmitters. Merkel endings are thought to be slow-adapting mech - anoreceptors, responsive to sustained pressure and sensitive to the edges of applied objects. Their functions are controversial, however, and likely to be more varied. ENCAPSULATED ENDINGS Encapsulated endings are a major group of special endings that includes lamellated corpuscles of various kinds (e.g. Meissner’s, Pacinian), Golgi tendon organs, neuromuscular spindles and Ruffini endings (see Fig. 3.27). They exhibit considerable variety in their size, shape and distribu - tion but share a common feature: namely, that each axon terminal is encapsulated by non-excitable cells (Proske and Gandevia 2012). Interoceptors include vascular chemoreceptors, e.g. the carotid body, and baroceptors, which are concerned with the regulation of blood flow and pressure and the control of respiration. FREE NERVE ENDINGS Sensory endings that branch to form plexuses occur in many sites (see Fig. 3.27). They occur in all connective tissues, including those of the dermis, fasciae, capsules of organs, ligaments, tendons, adventitia of blood vessels, meninges, articular capsules, periosteum, perichon - drium, Haversian systems in bone, parietal peritoneum, walls of viscera and the endomysium of all types of muscle. They also innervate the epithelium of the skin, cornea, buccal cavity, and the alimentary and respiratory tracts and their associated glands. Within epithelia, free sensory endings lack Schwann cell ensheathment and are enveloped instead by epithelial cells. Afferent fibres from free terminals may be myelinated or unmyelinated but are always of small diameter and low conduction velocity. When afferent axons are myelinated, their termi - nal arborizations lack a myelin sheath. These terminals serve several sensory modalities. In the dermis, they may be responsive to moderate cold or heat (thermoreceptors); light mechanical touch (mechanore - ceptors); damaging heat, cold or deformation (unimodal nociceptors); and damaging stimuli of several kinds (polymodal nociceptors). Similar fibres in deeper tissues may also signal extreme conditions, which are experienced, as with all nociceptors, as ache or pain. Free endings in the cornea, dentine and periosteum may be exclusively nociceptive.Fig. 3.27 Some major types of sensory ending of general afferent fibres (omitting neuromuscular, neurotendinous and hair-related types). The traces below each type of ending indicate (top) their response (firing rate (vertical lines) and adaption with time) to an appropriate stimulus (below) of the duration indicated. The Pacinian corpuscle’s response to vibration (rapid sequence of on–off stimuli) is also shown. Free endings: Rapidly adapting mechanoreceptor Thermoreceptor (hot and cold) Nociceptor Rapidly adapting ‘field’ mechanoreceptor (Meissner’s corpuscle)Rapidly adapting lamellated (Pacinian) corpuscle Type II Slowly adapting mechanoreceptor (Ruffini ending)Type I Slowly adapting mechanoreceptor (Merkel cell ending)

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Sensory endings 61 CHAPTER 3 into the capsule or core, so that it is not clearly defined in mature cor - puscles. The core consists of approximately 60 bilateral, compacted lamellae lying on both sides of a central nerve terminal. Each corpuscle is supplied by a myelinated axon, which initially loses its myelin sheath and subsequently loses its ensheathing Schwann cell at its junction with the core. The naked axon runs through the central axis of the core and ends in a slightly expanded bulb. It is in contact with the innermost core lamellae, is transversely oval and sends short projections of unknown function into clefts in the lamellae. The axon contains numerous large mitochondria, and minute vesicles, approximately 5 nm in diameter, which aggregate opposite the clefts. The cells of the capsule and core lamellae are thought to be specialized fibroblasts but some may be Schwann cells. Elastic fibrous tissue forms an overall external capsule to the corpuscle. Pacinian corpuscles are supplied by capillaries that accompany the axon as it enters the capsule. Pacinian corpuscles act as very rapidly adapting mechanoreceptors. They respond only to sudden disturbances and are especially sensitive to very-high-frequency vibration. The rapidity may be partly due to the lamellated capsule acting as a high pass frequency filter, damping slow distortions by fluid movement between lamellar cells. Groups of cor - puscles respond to pressure changes, e.g. on grasping or releasing an object. Ruffini endings Ruffini endings are slowly adapting mechanoreceptors. They are found in the dermis of thin, hairy skin, where they function as dermal stretch receptors and are responsive to maintained stresses in dermal collagen. They consist of the highly branched, unmyelinated endings of myeli - nated afferents. They ramify between bundles of collagen fibres within a spindle-shaped structure, which is enclosed partly by a fibrocellular sheath derived from the perineurium of the nerve. Ruffini endings appear electrophysiologically similar to Golgi tendon organs, which they resemble, although they are less organized structurally. Similar structures appear in joint capsules (see below). Golgi tendon organs Golgi tendon organs are found mainly near musculotendinous junc - tions (Fig. 3.30), where more than 50 may occur at any one site. Each terminal is closely related to a group of muscle fibres (up to 20) as they insert into the tendon. Golgi tendon organs are approximately 500 µm long and 100 µm in diameter, and consist of small bundles of tendon Meissner’s corpuscles Meissner’s corpuscles are found in the dermal papillae of all parts of the hand and foot, the anterior aspect of the forearm, the lips, palpebral conjunctiva and mucous membrane of the apical part of the tongue. They are most concentrated in thick hairless skin, especially of the finger pads, where there may be up to 24 corpuscles per cm 2 in young adults. Mature corpuscles are cylindrical in shape, approximately 80 µm long and 30 µm across, with their long axes perpendicular to the skin surface. Each corpuscle has a connective tissue capsule and central core com - posed of a stack of flat modified Schwann cells ( Fig. 3.28). Meissner’s corpuscles are rapidly adapting mechanoreceptors, sensitive to shape and textural changes in exploratory and discriminatory touch; their acute sensitivity provides the neural basis for reading Braille text. Pacinian corpuscles Pacinian corpuscles are situated subcutaneously in the palmar and plantar aspects of the hand and foot and their digits, the external geni - talia, arm, neck, nipple, periosteal and interosseous membranes, and near joints and within the mesenteries ( Fig. 3.29). They are oval, spheri - cal or irregularly coiled and measure up to 2 mm in length and 100–500 µm or more across; the larger ones are visible to the naked eye. Each corpuscle has a capsule, an intermediate growth zone and a central core that contains an axon terminal. The capsule is formed by approximately 30 concentrically arranged lamellae of flat cells approxi - mately 0.2 µm thick (see Fig. 3.28). Adjacent cells overlap and succes - sive lamellae are separated by an amorphous proteoglycan matrix that contains circularly orientated collagen fibres, closely applied to the surfaces of the lamellar cells. The amount of collagen increases with age. The intermediate zone is cellular and its cells become incorporated Fig. 3.28 A tactile Meissner’s corpuscle in a dermal papilla in the skin, demonstrated using the modified Bielschowsky silver stain technique. (Courtesy of Professor N Cauna, University of Pittsburgh.) Epidermis Tactile corpuscle Fig. 3.29 A Pacinian corpuscle in human dermis. (Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.) Fig. 3.30 The structure and innervation of a Golgi tendon organ. For clarity, the perineurium and endoneurium have been omitted to show the distribution of nerve fibres ramifying between the collagen fibre bundles of the tendon.

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NERvOuS SySTEm 62 SECTION 1 acceleration. Moreover, they are under complex central control; efferent (fusimotor) nerve fibres, by regulating the strength of contraction, can adjust the length of the intrafusal fibres and thereby the responsiveness of spindle sensory endings. In summary, the organization of spindles allows them to monitor muscle conditions actively in order to compare intended and actual movements, and to provide a detailed input to spinal, cerebellar, extrapyramidal and cortical centres about the state of the locomotor apparatus. JOINT RECEPTORS The arrays of receptors situated in and near articular capsules provide information on the position, movements and stresses acting on joints. fibres enclosed in a delicate capsule. The collagen bundles (intrafusal fasciculi) are less compact than elsewhere in the tendon, the collagen fibres are smaller and the fibroblasts larger and more numerous. A single, thickly myelinated 1b afferent nerve fibre enters the capsule and divides. Its branches, which may lose their ensheathing Schwann cells, terminate in leaf-like enlargements containing vesicles and mitochon - dria, which wrap around the tendon. A basal lamina or process of Schwann cell cytoplasm separates the nerve terminals from the collagen bundles that constitute the tendon. Golgi tendon organs are activated by passive stretch of the tendon but are much more sensitive to active contraction of the muscle. They are important in providing propriocep - tive information that complements the information coming from neu-romuscular spindles. Their responses are slowly adapting and they signal maintained tension. Neuromuscular spindles Neuromuscular spindles are mechanosensors essential for propriocep - tion (Boyd 1985). Each spindle contains a few small, specialized intrafusal muscle fibres, innervated by both sensory and motor nerve fibres (Figs 3.31–3.32). The whole is surrounded equatorially by a fusiform spindle capsule of connective tissue, consisting of an outer perineurium-like sheath of flattened fibroblasts and collagen, and an inner sheath that forms delicate tubes around individual intrafusal fibres (Fig. 3.33). A gelatinous fluid rich in glycosaminoglycans fills the space between the two sheaths. There are usually 5–14 intrafusal fibres (the number varies between muscles) and two major types of fibre, nuclear bag and nuclear chain fibres, which are distinguished by the arrangement of nuclei in their sarcoplasm. In nuclear bag fibres, an equatorial cluster of nuclei makes the fibre bulge slightly, whereas the nuclei in nuclear chain fibres form a single axial row. Nuclear bag fibres are subdivided into bag1 and bag2 fibres, are greater in diameter than chain fibres and extend beyond the surrounding capsule to the endomysium of nearby extrafusal muscle fibres. Nuclear chain fibres are attached at their poles to the capsule or to the sheaths of nuclear bag fibres. The intrafusal fibres resemble typical skeletal muscle fibres, except that the zone of myofibrils is thin around the nuclei. Dynamic bag1 fibres generally lack M lines, possess little sarcoplasmic reticulum, and have an abundance of mitochondria and oxidative enzymes, but little glycogen. Static bag2 fibres have distinct M lines and abundant glyco - gen. Nuclear chain fibres have marked M lines, sarcoplasmic reticulum and T-tubules, and abundant glycogen, but few mitochondria. Each fibre type carries distinct myosin heavy chain isoforms. These variations reflect the contractile properties of different intrafusal fibres. Muscle spindles receive two types of sensory innervation via the unmyelinated terminations of large myelinated axons. Primary (anulo - spiral) endings are equatorially placed and form spirals around the nucleated parts of intrafusal fibres. They are the endings of large sensory fibres (group Ia afferents), each of which sends branches to a number of intrafusal muscle fibres. Each terminal lies in a deep sarcolemmal groove in the spindle plasma membrane beneath its basal lamina. Secondary (flower spray) endings, which may be spray-shaped or anular, are largely confined to bag2 and nuclear chain fibres, and are the branched terminals of somewhat thinner myelinated (group II) affer - ents. They are varicose and spread in a narrow band on both sides of the primary endings. They lie close to the sarcolemma, though not in grooves. In essence, primary endings are rapidly adapting, while second - ary endings have a regular, slowly adapting response to static stretch. There are three types of motor endings in muscle spindles. Two are from fine, myelinated, fusimotor ( γ) efferents and one is from myeli - nated (β) efferent collaterals of axons that supply extrafusal slow twitch muscle fibres. The fusimotor efferents terminate nearer the equatorial region, where their terminals either resemble the motor end-plates of extrafusal fibres (plate endings) or are more diffuse (trail endings). Stimulation of the fusimotor and β-efferents causes contraction of the intrafusal fibres and, consequently, activation of their sensory endings. Muscle spindles signal the length of extrafusal muscle both at rest and throughout contraction and relaxation, the velocity of their con - traction and changes in velocity. These modalities may be related to the different behaviours of the three major types of intrafusal fibre and their sensory terminals. The sensory fusimotor endings of one type of nuclear bag fibre (dynamic bag1) are particularly concerned with signalling rapid changes in length that occur during movement, whilst those of the second bag fibre type (static bag2) and of chain fibres are less responsive to movement. These elements can therefore detect complex changes in the state of the extrafusal muscle surrounding spindles and can signal fluctuations in length, tension, velocity of length change and Fig. 3.31 A neuromuscular spindle, showing nuclear bag and nuclear chain fibres within the spindle capsule (green); these are innervated by the sensory anulospiral and ‘flower spray’ afferent fibre endings (blue) and by the γ and β fusimotor (efferent fibre) endings (red). The β efferent fibres are collaterals of fibres innervating extrafusal slow twitch muscle cells (M). External capsule Internal capsule Nuclear bag fibre Nuclear chain fibre Subcapsular space Primary (anulospiral) ending of group 1a afferent fibre Secondary (flower spray) ending ofgroup II afferent fibre Trail ending ofγ-efferent fibre Plate ending of γ-efferent fibre Plate ending ofM β-efferent fibre

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Neuromuscular junctions 63 CHAPTER 3 deeper layers and other articular structures (e.g. the fat pad of the tem - poromandibular joint). They are rapidly adapting, low-threshold mech- anoreceptors, sensitive to movement and pressure changes, and they respond to joint movement and transient stresses in the joint capsule. They are supplied by myelinated afferent axons but are probably not involved in the conscious awareness of joint sensation. Type III endings are identical to Golgi tendon organs in structure and function; they occur in articular ligaments but not in joint capsules. They are high-threshold, slowly adapting receptors and may serve, at least in part, to prevent excessive stresses at joints by reflex inhibition of the adjacent muscles. They are innervated by large myelinated affer - ent axons. Type IV endings are free terminals of myelinated and unmyelinated axons that ramify in articular capsules and the adjacent fat pads, and around the blood vessels of the synovial layer. They are high-threshold, slowly adapting receptors and are thought to respond to excessive movements, providing a basis for articular pain. NEUROMUSCULAR JUNCTIONS SKELETAL MUSCLE The most intensively studied effector endings are those that innervate muscle, particularly skeletal muscle. All neuromuscular (myoneural) junctions are axon terminals of motor neurones. They are specialized for the release of neurotransmitter on to the sarcolemma of skeletal muscle fibres, causing a change in their electrical state that leads to contraction. Each axon branches near its terminal to innervate from several to hundreds of muscle fibres, the number depending on the precision of motor control required (Shi et al 2012). The detailed structure of a motor terminal varies with the type of muscle innervated. Two major types of ending are recognized, innervat - ing either extrafusal muscle fibres or the intrafusal fibres of neuromus - cular spindles. In the former type, each axonal terminal usually ends midway along a muscle fibre in a discoidal motor end-plate ( Fig. 3.34A), and usually initiates action potentials that are rapidly con - ducted to all parts of the muscle fibre. In the latter type, the axon gives off numerous branches that form a cluster of small expansions extend - ing along the muscle fibre; in the absence of propagated muscle excita - tion, these excite the fibre at several points. Both types of ending are associated with a specialized receptive region of the muscle fibre, the sole plate, where a number of muscle cell nuclei are grouped within the granular sarcoplasm. The sole plate contains numerous mitochondria, endoplasmic retic - ulum and Golgi complexes. The terminal branches of the axon are plugged into shallow grooves in the surface of the sole plate (primary clefts), from where numerous pleats extend for a short distance into the underlying sarcoplasm (secondary clefts) ( Fig. 3.34B,C). The axon ter - minal contains mitochondria and many clear, 60 nm spherical vesicles similar to those in presynaptic boutons, which are clustered over the zone of membrane apposition. It is ensheathed by Schwann cells whose cytoplasmic projections extend into the synaptic cleft. The plasma membranes of the axon terminal and the muscle cell are separated by a 30–50 nm gap and an interposed basal lamina, which follows the surface folding of the sole-plate membrane into the secondary clefts. Endings of fast and slow twitch muscle fibres differ in detail: the sarco - lemmal grooves are deeper, and the presynaptic vesicles more numer - ous, in the fast fibres. Junctions with skeletal muscle are cholinergic: the release of ACh changes the ionic permeability of the muscle fibre (Sine 2012). Cluster - ing of ACh receptors at the neuromuscular junction depends in part on the presence in the muscle basal lamina of agrin, which is secreted by the motor neurone, and is important in establishing the postjunctional molecular machinery. When the depolarization of the sarcolemma reaches a particular threshold, it initiates an action potential in the sarcolemma, which is then propagated rapidly over the whole cell surface and also deep within the fibre via the invaginations (T-tubules) of the sarcolemma, causing contraction. The amount of ACh released by the arrival of a single nerve impulse is sufficient to trigger an action potential. However, because ACh is very rapidly hydrolysed by the enzyme AChE, present at the sarcolemmal surface of the sole plate, a single nerve impulse only gives rise to one muscle action potential, i.e. there is a one-to-one relationship between neuronal and muscle action potentials. Thus the contraction of a muscle fibre is controlled by the firing frequency of its motor neurone. Neuromuscular junctions are partially blocked by high concentra - tions of lactic acid, as in some types of muscle fatigue.Structural and functional studies have demonstrated at least four types of joint receptor; their proportions and distribution vary with site. Three are encapsulated endings, the fourth a free terminal arborization. Type I endings are encapsulated corpuscles of the slowly adapting mechanoreceptor type and resemble Ruffini endings. They lie in the superficial layers of the fibrous capsules of joints in small clusters and are innervated by myelinated afferent axons. Being slowly adapting, they provide awareness of joint position and movement, and respond to patterns of stress in articular capsules. They are particularly common in joints where static positional sense is necessary for the control of posture (e.g. hip, knee). Type II endings are lamellated receptors and resemble small versions of the large Pacinian corpuscles found in general connective tissue. They occur in small groups throughout joint capsules, particularly in the Fig. 3.32 Nuclear bag and nuclear chain fibres in a neuromuscular spindle. Dynamic β- and γ-efferents innervate dynamic bag1 intrafusal fibres, whereas static β- and γ-efferents innervate static bag2 and nuclear chain intrafusal fibres. Dynamic γ-efferent Static γ-efferent Afferent fibres Static γ-efferent Static β-efferent Dynamic β-efferentII II Ia Collaterals to extrafusal muscleDynamic bag1 fibreStatic bag2 fibre Long-chain fibre Short-chain fibres Fig. 3.33 A neuromuscular spindle in transverse section in a human extraocular muscle. The spindle capsule (C) encloses intrafusal fibres (IF) of varying diameters. Typical muscle fibres (M) in transverse section are shown above the spindle. Toluidine blue stained resin section. C CIFC CMM IF

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NERvOuS SySTEm 64 SECTION 1 AUTONOMIC MOTOR TERMINATIONS Autonomic neuromuscular junctions differ in several important ways from the skeletal neuromuscular junction and from synapses in the CNS and PNS. There is no fixed junction with well-defined pre- and postjunctional specializations. Unmyelinated, highly branched, post - ganglionic autonomic axons become beaded or varicose as they reach the effector smooth muscle. These varicosities are not static but move along axons. They are packed with mitochondria and vesicles contain - ing neurotransmitters, which are released from the varicosities during conduction of an impulse along the axon. The distance (cleft) between the varicosity and smooth muscle membrane varies considerably depending on the tissue, from 20 nm in densely innervated structures such as the vas deferens to 1–2 µm in large elastic arteries. Unlike skel - etal muscle, the effector tissue is a muscle bundle rather than a single cell. Gap junctions between individual smooth muscle cells are low- resistance pathways that allow electronic coupling and the spread of activity within the effector bundle; they vary in size from punctate junc - tions to junctional areas of more than 1 µm in diameter. Adrenergic sympathetic postganglionic terminals contain dense- cored vesicles. Cholinergic terminals, which are typical of all parasym - pathetic and some sympathetic endings, contain clear spherical vesicles like those in the motor end-plates of skeletal muscle. A third category of autonomic neurones has non-adrenergic, non-cholinergic endings that contain a wide variety of chemicals with transmitter properties. ATP is a neurotransmitter at these terminals, which express purinergic receptors (Burnstock et al 201 1). The axons typically contain large, 80–200 nm, dense opaque vesicles, congregated in varicosities at inter - vals along their length. These terminals are formed in many sites, including the lungs, blood vessel walls, the urogenital tract and the external muscle layers and sphincters of the gastrointestinal tract. In the intestinal wall, neuronal somata lie in the myenteric plexus, and their axons spread caudally for a few millimetres, mainly to innervate circular muscle. Purinergic neurones are under cholinergic control from pregan - glionic sympathetic neurones. Their endings mainly hyperpolarize smooth muscle cells, causing relaxation, e.g. preceding peristaltic waves, opening sphincters and, probably, causing reflex distension in gastric filling. Autonomic efferents innervate exocrine glands, myoepithelial cells, adipose tissue (noradrenaline (norepinephrine) released from postganglionic sympathetic axons binds to β 3-receptors on adipocytes to stimulate lipolysis) and the vasculature and parenchymal fields of lymphocytes and associated cells in several lymphoid organs, including the thymus, spleen and lymph nodes. CNS–PNS TRANSITION ZONE The transition between CNS and PNS usually occurs some distance from the point at which nerve roots emerge from the brain or the spinal cord. The segment of root that contains components of both CNS and PNS tissue is called the CNS–PNS transition zone (TZ). All axons in the PNS, other than postganglionic autonomic neurones, cross such a TZ. Macroscopically, as a nerve root is traced towards the spinal cord or the brain, it splits into several thinner rootlets that may, in turn, subdivide into minirootlets. The TZ is located within either rootlet or minirootlet (Fig. 3.35). The arrangement of roots and rootlets varies according to whether the root trunk is ventral, dorsal or cranial. Thus, in dorsal roots, the main root trunk separates into a fan of rootlets and minirootlets that enter the spinal cord in sequence along the dorsolateral sulcus. In certain cranial nerves, the minirootlets come together central to the TZ and enter the brain as a stump of white matter. Motor axon Schwann cell Muscle cell nucleus Motor end-plate with synaptic vesiclesMuscle sole plate Motor end-plateA B CFig. 3.34 The neuromuscular junction. A, Whole-mount preparation of teased skeletal muscle fibres (pale, faintly striated, diagonally orientated structures). The terminal part of the axon (silver-stained, brown) branches to form motor end-plates on adjacent muscle fibres. The sole plate recesses in the sarcolemma, into which the motor end-plates fit, are demonstrated by the presence of acetylcholinesterase (shown by enzyme histochemistry, blue). B, The axonal motor end-plate and the deeply infolded sarcolemma. C, Electron micrograph showing the expanded motor end-plate of an axon filled with vesicles containing synaptic transmitter (ACh) (above); the deep infoldings of the sarcolemmal sole plate (below) form subsynaptic gutters. (A, Courtesy of Dr Norman Gregson, Division of Neurology, GKT School of Medicine, London. C, Courtesy of Professor DN Landon, Institute of Neurology, University College London.)

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Conduction of the nervous impulse 65 CHAPTER 3 thought to prevent cell mixing at these interfaces not only by helping dorsal root ganglion afferents navigate their path to targets in the spinal cord but also by inhibiting motoneurone cell bodies exiting to the periphery. For further reading, see Zujovic et al (201 1). CONDUCTION OF THE NERVOUS IMPULSE All cells generate a steady electrical potential across their plasma mem - brane (the membrane potential). This potential is generated by an uneven distribution of potassium ions across the membrane (higher in the intracellular compartment than in the extracellular compartment), and by a selective permeability of the membrane for potassium ( Fig. 3.36). The distribution of sodium ions is opposite to that for potassium ions, but at rest the sodium conductance of the membrane is low. In Microscopically, the TZ is characterized by an axial CNS compart - ment surrounded by a PNS compartment. The zone lies more peripher - ally in sensory nerves than in motor nerves, but in both, the apex of the TZ is described as a glial dome, whose convex surface is usually directed distally. The centre of the dome consists of fibres with a typical CNS organization, surrounded by an outer mantle of astrocytes (cor - responding to the glia limitans). From this mantle, numerous glial processes project into the endoneurial compartment of the peripheral nerve, where they interdigitate with its Schwann cells. The astrocytes form a loose reticulum through which axons pass. Peripheral myeli - nated axons usually cross the zone at a node of Ranvier, which is here termed a PNS–CNS compound node. Boundary cap (BC) cells are neural crest derivatives that form tran - sient, discrete clusters localized at the presumptive dorsal root entry zones and motor exit points of the embryonic spinal cord. They are Fig. 3.35 The nerve root–spinal cord junction. A–G, Different CNS–PNS borderline arrangements. A, A pointed borderline. The extent of the transitional zone (TZ) is indicated. B–G, Glial fringe omitted. B, A concave borderline (white line) and inverted TZ. C, A flat borderline situated at the level of the root (R)–spinal cord junction. D and E, A convex, dome-shaped borderline; the CNS expansion into the rootlet is moderate in D and extensive in E. F, The root (R) splits into rootlets (r), each with its own TZ and attaching separately to the spinal cord (SC). G, The arrangement found in several cranial nerve roots (e.g. vestibulocochlear nerve). The PNS component of the root separates into a bundle of closely packed minirootlets, each equipped with a TZ. The minirootlets reunite centrally. BS, brainstem. (Adapted with permission from Dyck PJ, Thomas PK, Griffin JW, et al (eds) Peripheral Neuropathy, 3rd ed. Philadelphia: Saunders, 1993.)B C D E AR R RR F GBSR R SCr1r2r3TZRNerve root CNS tissue Glial fringeMantle zone Fig. 3.36 The types of change in electrical potential that can be recorded across the cell membrane of a motor neurone at the points indicated. Excitatory and inhibitory synapses on the surfaces of the dendrites and soma cause local graded changes of potential that summate at the axon hillock and may initiate a series of all-or-none action potentials, which in turn are conducted along the axon to the effector terminals. +40 mV -80 mV0Membrane potential Excitation (depolarization)Inhibition(hyperpolarization)Net effect at axonhillock is excitationGraded potentialsAll-or-none action potentials generated at nodes along axon Excitatory axonInhibitory axon ConductionTime

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NERvOuS SySTEm 66 SECTION 1 tion of neighbouring membrane. Sodium channels within the newly depolarized segment open and positively charged sodium ions enter, driving the local potential inside the axon towards positive values. This inward current in turn depolarizes the neighbouring, downstream, non- depolarized membrane, and the cyclic propagation of the action poten - tial is completed. Several milliseconds after the action potential, the sodium channels are inactivated, a period known as the refractory period. The length of the refractory period determines the maximum frequency at which action potentials can be conducted along a nerve fibre; it varies in different neurones and affects the amount of informa - tion that can be carried by an individual fibre. Myelinated fibres are electrically insulated by their myelin sheaths along most of their lengths, except at nodes of Ranvier. The distance between nodes, referred to as the internodal distance, is directly related to axon diameter and varies between 0.2 and 2.0 mm. Voltage-gated sodium channels are clustered at nodes, and the nodal membrane is the only place where high densities of inward sodium current can be generated across the axon membrane. Conduction in myelinated axons is self-propagating, but instead of physically adjacent regions of mem - brane acting to excite one another (as occurs along unmyelinated axons), it is the depolarization occurring in the neighbouring upstream node that excites a node to threshold. Reaching threshold causes the sodium channels at the node to open and generate inward sodium current, but instead of this acting on the adjacent membrane, the high resistance and low capacitance of the myelin sheath directs the current towards the next downstream node, exciting it to threshold and com - pleting the cycle. The action potential thus jumps from node to node, a process known as saltatory conduction, which greatly increases the conduction velocity. A number of disorders of the CNS and PNS include demyelination as a characteristic feature. Perhaps most common amongst these is multiple sclerosis, which is characterized by primary demyelination at scattered sites within the CNS (it is now recognized that axonal loss also contributes to the progression of multiple sclerosis). Primary demyelination is the loss of the myelin sheath with axonal preservation, and is usually segmental, i.e. it rarely extends along the entire length of an affected axon. The phenomenon is associated with conduction block because the newly exposed, previously internodal, axolemma contains relatively few voltage-sensitive Na + channels. There is experimental evi - dence that conduction can be restored in some demyelinated axons, and experimental and clinical evidence that remyelinated axons can conduct at near-normal speeds, because even though their sheaths are thinner than the original myelin sheaths, the safety factor (i.e. the factor by which the outward current at a quiescent node next to an excited node exceeds the minimum current required to evoke a response) is greater than 1. The myelin loss that occurs in the early stages of Walle - rian degeneration in both CNS and PNS, usually distal to a site of trauma but also in response to a prolonged period of ischaemia or exposure to a neuronotoxic substance, is accompanied by axonal degen - eration (the term secondary demyelination is sometimes used to describe this form of myelin loss). Axonal conduction is naturally unidirectional, from dendrites and soma to axon terminals. When an action potential reaches the axonal terminals, it causes depolarization of the presynaptic membrane, and as a result, quanta of neurotransmitter (which correspond to the content of individual vesicles) are released to change the degree of excitation of the next neurone, muscle fibre or glandular cell.neurones this membrane potential is known as the resting potential, and amounts to approximately −60 mV (potential inside the cell meas - ured relative to the outside of the cell). Non-excitable cells have an even higher membrane potential. Neurones receive, conduct and transmit information by changes in membrane conductance for sodium, potas - sium, calcium or chloride ions. Increase in the sodium or calcium conductance causes an influx of these ions and results in a depolariza- tion of the cell, while chloride influx or potassium efflux results in hyperpolarization. Plasma membrane permeability to these ions is altered by the opening or closing of ion-specific transmembrane chan - nels, triggered by voltage changes or chemical signals such as transmit - ters (Catterall 2010). Chemically triggered ionic fluxes may be either direct, where the chemical agent (neurotransmitter) binds to the channel itself to cause it to open, or indirect, where the neurotransmitter is bound by a trans - membrane receptor molecule that activates a complex second messen - ger system within the cell to open separate transmembrane channels. Electrically induced changes in membrane potential depend on the presence of voltage-sensitive ion channels, which, when the transmem - brane potential reaches a critical level, open to allow the influx or efflux of specific ions. In all cases, the channels remain open only transiently, and the numbers that open and close determine the total flux of ions across the membrane (Bezanilla 2008). The types and concentrations of transmembrane channels and related proteins, and therefore the electrical activity of the membranes, vary in different parts of the cell. Dendrites and neuronal somata depend mainly on neurotransmitter action and show graded potentials, whereas axons have voltage-gated channels that give rise to action potentials. In graded potentials, a flow of current occurs when a synapse is activated; the influence of an individual synapse on the membrane potential of neighbouring regions decreases with distance. Thus syn - apses on the distal tips of dendrites may, on their own, have relatively little effect on the membrane potential of the cell body. The electrical state of a neurone therefore depends on many factors, including the numbers and positions of thousands of excitatory and inhibitory syn - apses, their degree of activation, and the branching pattern of the den - dritic tree and geometry of the cell body. The integrated activity directed towards the neuronal cell body is converted to an output directed away from the soma at the site where the axon leaves the cell body, at its junction with the axon hillock. Voltage-sensitive channels are concen- trated at this trigger zone, the axon initial segment, and when this region is sufficiently depolarized, an action potential is generated and is subsequently conducted along the axon. ACTION POTENTIAL The action potential is a brief, self-propagating reversal of membrane polarity. It depends on an initial influx of sodium ions, which causes a reversal of polarity to about + 20 mV, followed by a rapid return towards the resting potential as potassium ions flow out. The rapid reversal process is completed in approximately 0.5 msec, followed by a slower recovery phase of up to 5 msec, when the resting potential is even hyperpolarized. Once the axon hillock reaches threshold, propagation of the action potential is independent of the initiating stimulus; thus the size and duration of action potentials are always the same (described as all-or-none) for a particular neurone, no matter how much a stimulus may exceed the threshold value. Once initiated, an action potential spreads spontaneously and at a relatively constant velocity, within the range of 4–120 m/s. Conduction velocity depends on a number of factors related to the way in which the current spreads, e.g. axonal cross-sectional area, the numbers and positioning of ion channels, and membrane capacitance (influenced particularly by the presence of myelin). In axons lacking myelin, action potential conduction is analogous to a flame moving along a fuse. Just as each segment of fuse is ignited by its upstream neighbour, each segment of axon membrane is driven to threshold by the depolariza -Fig. 3.1 A section through the human cerebellum stained to show the arrangement in the brain of the central white matter and the highly folded outer grey matter.  Bonus  e-book  image

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67 CHAPTER 3Key references KEY REFERENCES Finger S 2001 Origins of Neuroscience: A History of Explorations into Brain Function. New York: Oxford University Press. A historic introduction to the neuroscience field. Kandel ER, Schwartz JH, Jessell TM et al 2012 Principles of Neural Science, 5th ed. New York: McGraw–Hill. A basic but comprehensive neuroscience textbook Kempermann G 201 1 Adult Neurogenesis 2. New York: Oxford University Press. A summary of the knowledge on adult neurogenesis. Kettenmann H, Ransom BR 2012 Neuroglia. New York: Oxford University Press.A comprehensive textbook on glial cells. Levitan IB, Kaczmarek LK 2001 The Neuron: Cell and Molecular Biology. New York: Oxford University Press. A basic neuroscience textbook with the focus on neurones. Nicholls JG, Martin AR, Fuchs PA et al 201 1 From Neuron to Brain, 5th ed. Sunderland, MA: Sinauer Associates. A basic and comprehensive neuroscience textbook.Sakmann B, Neher E 2009 Single-channel Recording. New York: Springer. An introduction to the patch-clamp technique and electrophysiology. Sanes DH, Reh TA, Harris WA 201 1 Development of the Nervous System, 3rd ed. Oxford: Elsevier, Academic Press. A textbook on developmental neurobiology. Shepherd GM 2003 The Synaptic Organization of the Brain. New York: Oxford University Press. A description of the circuitry of the brain. Squire L, Kandel E 2008 Memory: From Mind to Molecules. Greenwood Village, CO: Roberts.A description of the mechanism of memory formation. Squire L, Berg D, Bloom FE et al 2012 Fundamental Neuroscience, 4th ed. Oxford: Elsevier, Academic Press. A basic but comprehensive neuroscience textbook.

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Nervous system 67.e1 CHAPTER 3 REFERENCES Abbott NJ, Rönnbäck L, Hansson E 2006 Astrocyte–endothelial interactions at the blood–brain barrier. Nature Rev Neurosci 7:41–53. Albuquerque EX, Pereira EFR, Alkondon M et al 2009 Mammalian nicotinic acetylcholine receptors: from structure to function. Phys Rev 89: 73–120. Anthony DC, Pitossi FJ 2013 Special issue commentary: the changing face of inflammation in the brain. Mol Cell Neurosci 53:1–5. Azevedo FA, Carvalho LR, Grinberg LT et al 2009 Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol 513:532–41. Bakhti M, Aggarwal S, Simons M 2014 Myelin architecture: zippering mem - branes tightly together. Cell Mol Life Sci 71:1265–77. Barrera NP, Edwardson JM 2008 The subunit arrangement and assembly of ionotropic receptors. Trends Neurosci 31:569–76. Bender KJ, Trussell LO 2012 The physiology of the axon initial segment. Annu Rev Neurosci 35:249–65. 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NERvOuS SySTEm 67.e2 SECTION 1 Nicholls JG, Martin AR, Fuchs PA et al 201 1 From Neuron to Brain, 5th ed. Sunderland, MA: Sinauer Associates. A basic and comprehensive neuroscience textbook. Nishiyama A, Komitova M, Suzuki R et al 2009 Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity. Nature Rev Neurosci 10: 9–22. Nolte J 2008 The Human Brain: An Introduction to Functional Anatomy, 6th ed. Edinburgh: Elsevier, Mosby; Ch. 9, pp. 197–222. Norrmén C, Suter U 2013 Akt/mTOR signalling in myelination. Biochem Soc Trans 41:944–50. Pakkenberg B, Gundersen HJG 1988 Total number of neurons and glial cells in human brain nuclei estimated by the disector and the fractionator. J Microsc 150:1–20. Parpura V, Zorec R 2010 Gliotransmission: exocytotic release from astrocytes. Brain Res Rev 63:83–92. Peles E, Salzer JL 2000 Molecular domains of myelinated axons. Curr Op Neurobiol 10:558–65. Perea G, Navarrete M, Araque A 2009 Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 32:421–31. Pereira JA, Lebrun-Julien F, Suter U 2012 Molecular mechanisms regulating myelination in the peripheral nervous system. Trends Neurosci 35: 123–34. Poliak S, Peles E 2003 The local differentiation of myelinated axons at nodes of Ranvier. Nat Rev Neurosci 4:968–80. Proske U, Gandevia SC 2012 The proprioceptive senses: their roles in signal - ing body shape, body position and movement, and muscle force. Physiol Rev 92:1651–97. Robel S, Berninger B, Goetz, M 201 1 The stem cell potential of glia: lessons from reactive gliosis. Nature Rev Neurosci 12:88–104. Ryan TJ, Grant SGN 2009 The origin and evolution of synapses. Nature Rev Neurosci 10:701–26. Sakmann B, Neher E 2009 Single-channel Recording. New York: Springer. An introduction to the patch-clamp technique and electrophysiology. Sanai N, Nguyen T, Ihrie RA et al 201 1 Corridors of migrating neurons in the human brain and their decline during infancy. Nature 478:382–6. Sanes DH, Reh TA, Harris WA 201 1 Development of the Nervous System, 3rd ed. Oxford: Elsevier, Academic Press. A textbook on developmental neurobiology.Schmieg N, Memendez G, Schiavo G et al 2014 Signalling endosomes in axonal transport: travel updates on the molecular highway. Semin Cell Dev Biol 27:32–43. Segal V, Vlachos A, Korkotian E 2010 The spine apparatus, synaptopodin, and dendritic spine plasticity. Neuroscientist 16:125–31. Seifert G, Schilling K, Steinhäuser C 2006 Astrocyte dysfunction in neuro - logical disorders: a molecular perspective. Nature Rev Neurosci 7: 194–206. Shah MM, Hammond RS, Hoffman DA 2010 Dendritic ion channel traffick - ing and plasticity. Trends Neurosci 33:307–16. Shepherd GM 2003 The Synaptic Organization of the Brain. New York: Oxford University Press.A description of the circuitry of the brain. Shi L, Fu AKY, Ip NY 2012 Molecular mechanisms underlying maturation and maintenance of the vertebrate neuromuscular junction. Trends Neurosci 35:441–53. Sine SM 2012 End-plate acetylcholine receptor: structure, mechanism, phar - macology, and disease. Phys Rev 92:1 189–234. Spruston N 2008 Pyramidal neurons: dendritic structure and synaptic inte - gration. Nature Rev Neurosci 9:206–21. Squire L, Kandel E 2008 Memory: From Mind to Molecules. Greenwood Village, CO: Roberts.A description of the mechanism of memory formation. Squire L, Berg D, Bloom FE et al 2012 Fundamental Neuroscience, 4th ed. Oxford: Elsevier, Academic Press.A basic but comprehensive neuroscience textbook. Suedhof TC 2012 The presynaptic active zone. Neuron 75:1 1–25. Tait MJ, Saadoun S, Bell BA et al 2008 Water movements in the brain: role of aquaporins. Trends Neurosci 31:37–43. Willard SS, Koochekpour S 2013 Glutamate, glutamate receptors, and down - stream signaling pathways. Int J Biol Sci 9:948–59. Wong RO, Ghosh A 2002 Activity-dependent regulation of dendritic growth and patterning. Nature Rev Neurosci 10:803–12. Zujovic V, Thibaud J, Bachelin C et al 201 1 Boundary cap cells are peripheral nervous system stem cells that can be redirected into central nervous system lineages. Proc Natl Acad Sci USA 108:10714–19.

Gray's Anatomy: 41st Edition

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68 SECTION 1 CHAPTER 4 Blood, lymphoid tissues and haemopoiesis defensive cells (white blood cells, or leukocytes). The latter include neutrophil, eosinophil and basophil granulocytes, B lymphocytes and monocytes. T lymphocytes develop in the thymus from bone marrow- derived progenitors. These cells all contribute to the immune system of the human (for an overview of the immune system, see Murphy (201 1)). Platelets are produced in the bone marrow as cellular fragments of megakaryocytes. Only erythrocytes and platelets are generally confined to the blood vascular system, whereas all leukocytes can leave the cir - culation and enter extravascular tissues. The numbers of cells doing so increases greatly during inflammation caused by local infections or tissue damage. The lymphoid tissues are the thymus, lymph nodes, spleen and the lymphoid follicles associated mainly with the alimentary and respira- tory tracts. Lymphocytes populate lymphoid tissues and are concerned with immune defence. Lymphoid tissue also contains supportive stro - mal cells, which are non-haemopoietic in origin (e.g. thymic epithe - lium); non-haemopoietic follicular dendritic cells of lymph nodes and splenic follicles; haemopoietically derived dendritic cells; and macro - phages of the mononuclear phagocyte system. Dendritic cells and blood monocyte-derived macrophages are found additionally in most tissues and organs, where they function as antigen-presenting cells (APCs). CELLS OF PERIPHERAL BLOOD ERYTHROCYTES Erythrocytes (red blood cells, RBCs) account for the largest proportion of blood cells (99% of the total number), with normal values of 4.1–6.0 × 106/µl in adult males and 3.9–5.5 × 106/µl in adult females. Polycythaemia (increased red cell mass) can occur in individuals living at high altitude, or pathologically in conditions resulting in arterial hypoxia. Reduction in red cell mass (anaemia) has many underlying causes but in rare instances can be due to structural defects in erythro- cytes (see below). Each erythrocyte is a biconcave disc (see Fig. 4.1; Fig. 4.2) with a mean diameter in dried smear preparations of 7.1 µm; in fresh prepara - tions the mean diameter is 7.8 µm, decreasing slightly with age. Mature erythrocytes lack nuclei. They are pale red by transmitted light, with Blood is an opaque fluid with a viscosity greater than that of water (mean relative viscosity 4.75 at 18°C), and a specific gravity of 1.06 at 15°C. It is bright red when oxygenated, in the systemic arteries, and dark red to purple when deoxygenated, in systemic veins. Blood is a mixture of a clear liquid, plasma and cellular elements, and consequently the hydrodynamic flow of blood in vessels behaves in a complex manner that is not entirely predictable by simple Newtonian equations. Plasma is a clear, yellowish fluid that contains many substances in solution or suspension: low-molecular-weight solutes give a mean freezing-point depression of 0.54°C. Plasma contains high concentra - tions of sodium and chloride ions, potassium, calcium, magnesium, phosphate, bicarbonate, traces of many other ions, glucose, amino acids and vitamins. It also includes high-molecular-weight plasma proteins, e.g. clotting factors, particularly prothrombin; immunoglobulins and complement proteins involved in immunological defence; glycopro - teins, lipoproteins, polypeptide and steroid hormones, and globulins for the transport of hormones and iron. The plasma is involved in the transport of most molecules that are released or secreted by cells in response to pathological or physiological stimuli and so the routine chemical analysis of plasma is of great diagnostic importance. There is increasing interest in using metabolomics approaches for the high- throughput analysis of small molecules or metabolites in the serum, as a potential aid to diagnosis and understanding of disease (Psychogios et al 201 1). The precipitation of the protein fibrin from plasma to form a clot (Fig. 4.1) is initiated by the release of specific materials from damaged cells and blood platelets in the presence of calcium ions. If blood or plasma samples are allowed to stand, they will separate into a clot and a clear yellowish fluid, the serum. Clot formation is prevented by removal of calcium ions, e.g. by addition of citrate, oxalate or various organic calcium chelators (EDTA, EGTA) to the sample. Heparin is also widely used as an anticlotting agent because it interferes with fibrin clot formation. In postnatal life, blood cells are formed in the bone marrow. Hae - mopoiesis produces red cells (erythrocytes) and a wide variety of Fig. 4.1 Erythrocytes enmeshed in filaments of fibrin in a clot. (Courtesy of Michael Crowder MD.) Fig. 4.2 A human heart muscle biopsy specimen, showing an erythrocyte within a capillary. The erythrocyte biconcave disc is typically electron- dense and almost fills the capillary lumen. (Courtesy of Dr Bart Wagner, Histopathology Department, Sheffield Teaching Hospitals, UK.)

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Cells of peripheral blood 69 CHAPTER 4 exposed on the aged erythrocyte. These lead to the cells being recog - nised and taken up by macrophages. Red cells are destroyed at the rate of 5 × 101 1 cells a day (or nearly 6 million a second) and are normally replaced from the bone marrow (see Fig. 4.12) at the same rate. Blood groups Over 300 red cell antigens are recognizable with specific antisera. They can interact with naturally occurring or induced antibodies in the plasma of recipients of an unmatched transfusion, causing agglutina - tion and lysis of the erythrocytes. Erythrocytes of a single individual carry several different types of antigen, each type belonging to an anti - genic system in which a number of alternative antigens are possible in different persons. So far, 19 major groups have been identified. They vary in their distribution frequencies between different populations, and include the ABO, Rhesus, MNS, Lutheran, Kell, Lewis, Duffy, Kidd, Diego, Cartwright, Colton, Sid, Scianna, Yt, Auberger, Ii, Xg, Indian and Dombrock systems. Clinically, the ABO and Rhesus groups are of most importance. Leukocytes also bear highly polymorphic antigens encoded by allelic gene variants. These belong to the group of major histocompatibility complex (MHC) antigens, also termed human leukocyte antigens (HLA) in humans. HLA class I antigens are expressed by all nucleated cells. Class II antigens are expressed on antigen-presenting cells (APCs) of the immune system, but can also be induced on many parenchymal cell types, e.g. after exposure to interferon. HLA class I and II antigens play important roles in cell–cell interactions in the immune system, particularly in the presentation of antigens to T lymphocytes by APCs. LEUKOCYTES Leukocytes (white blood cells) belong to at least five different categories (see Fig. 4.12) and are distinguishable by their size, nuclear shape and cytoplasmic inclusions. In practice, leukocytes are often divided into two main groups: namely, those with prominent stainable cytoplasmic granules, the granulocytes, and those without. Granulocytes This group consists of eosinophil granulocytes, with granules that bind acidic dyes such as eosin; basophil granulocytes, with granules that bind basic dyes strongly; and neutrophil granulocytes, with granules that stain only weakly with either type of dye. Granulocytes ( Fig. 4.3) all possess irregular or multilobed nuclei and belong to the myeloid series of blood cells (see Fig. 4.12). Neutrophil granulocytes Neutrophil granulocytes (neutrophils) are also referred to as polymor- phonuclear leukocytes (polymorphs) because of their irregularly paler centres because of their biconcave shape. The properties of their cell coat cause them to adhere to one another by their rims to form loose piles of cells (rouleaux). In normal blood, a few cells assume a shrunken, star-like, crenated form; this shape can be reproduced by placing normal biconcave erythrocytes in a hypertonic solution, which causes osmotic shrinkage. In hypotonic solutions erythrocytes take up water and become spherical; they may eventually lyse to release their haemoglobin (haemolysis), leaving red-cell ghosts. Erythrocytes have a plasma membrane that encloses mainly a single protein, haemoglobin, as a 33% solution. The plasma membrane of erythrocytes is 60% lipid and glycolipid, and 40% protein and glycoprotein. More than 15 classes of protein are present, including two major types. Glycophorins A and B (each with a molecular mass of approxi- mately 50 kDa) span the membrane, and their negatively charged car - bohydrate chains project from the outer surface of the cell. Their sialic acid groups confer most of the fixed charge on the cell surface. A second transmembrane macromolecule, band 3 protein, forms an important anion channel, exchanging bicarbonate for chloride ions across the membrane and allowing the release of CO 2 in the lungs. The filamentous protein, spectrin, is responsible for maintaining the shape of the erythrocyte. A dimer is formed of α1 and β1 spectrin monomers, and two dimers then come together to form a tetramer (Machnicka et al 2013). These are joined by junctional complexes that contain (among other proteins) ankyrin, short actin filaments, tropo - myosin and protein 4.1, forming a hexagonal lattice that supports the plasma membrane (Mankelow et al 2012). The junctional complex also interacts with transmembrane proteins. This structure gives the mem - brane great flexibility; red cells are deformable but regain their bicon - cave shape and dimensions after passing through the smallest capillaries, which are 4 µm in diameter (Mohandas and Gallagher 2008). Erythro - cyte membrane flexibility also contributes to the normally low viscosity of blood. Molecular defects in the cytoskeleton result in abnormalities of red cell shape, membrane fragility, premature destruction of eryth - rocytes in the spleen and haemolytic anaemia (Iolascon et al 1998). Fetal erythrocytes up to the fourth month of gestation differ mark - edly from those of adults, in that they are larger, are nucleated and contain a different type of haemoglobin (HbF). After this time they are progressively replaced by the adult type of cell. Haemoglobin Haemoglobin (Hb) is a globular protein with a molecular mass of 67 kDa. It consists of globulin molecules bound to haem, an iron- containing porphyrin group. The oxygen-binding power of haemo - globin is provided by the iron atoms of the haem groups, and these are maintained in the ferrous (Fe++) state by the presence of glutathione within the erythrocyte. The haemoglobin molecule is a tetramer, made up of four subunits, each a coiled polypeptide chain holding a single haem group. Mutations in the haemoglobin chains can result in a range of pathol - ogies (Forget and Bunn 2013). Lifespan Erythrocytes last between 100 and 120 days before being destroyed. As erythrocytes age, they become increasingly fragile, and their surface charges decrease as their content of negatively charged membrane glyco - proteins diminishes. The lipid content of their membranes also reduces. Aged erythrocytes are taken up by the macrophages of the spleen (Mebius and Kraal 2005) and liver sinusoids, usually without prior lysis, and are hydrolysed in phagocytic vacuoles where the haemoglobin is split into its globulin and porphyrin moieties. Globulin is further degraded to amino acids, which pass into the general amino-acid pool. Iron is removed from the porphyrin ring and either transported in the circulation bound to transferrin and used in the synthesis of new hae - moglobin in the bone marrow, or stored in the liver as ferritin or haemosiderin. The remainder of the haem group is converted in the liver to bilirubin and excreted in the bile. Haemoglobin that is released by destruction of erythrocytes in the body binds to haptoglobin, and is taken up via CD163 receptors expressed on the surface of macrophages (Kristiansen et al 2001). The recognition of effete erythrocytes by macrophages appears to take place by a number of mechanisms (Bratosin et al 1998). These include the exposure of phospholipids (such as phosphatidyl serine) that are normally found on the inner leaflet of the membrane bilayer, alterations in the carbohydrates expressed by the cells (most notably the loss of sialic acid) and the binding of autoantibodies to antigens Fig. 4.3 Neutrophil (N) and basophil (B) granulocytes within a renal glomerular capillary in a human kidney biopsy. The neutrophil nucleus is more segmented (four lobes are visible) and the granules are smaller and more electron-dense than in the basophil. (Courtesy of Dr Bart Wagner, Histopathology Department, Sheffield Teaching Hospitals, UK.) N B

Gray's Anatomy: 41st Edition

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Blood, lymphoid tissues and haemopoiesis 69.e1 CHAPTER 4 In normal blood, five types of polypeptide chain can occur: namely, α, β and two β-like polypeptides, γ and δ. A third, β-like η chain is restricted to early fetal development. Each haemoglobin molecule con - tains two α-chains and two others, so that several combinations, and hence a number of different types of haemoglobin molecule, are pos - sible. For example, haemoglobin A (HbA), which is the major adult class, contains 2 α- and 2 β-chains; a variant, HbA 2 with 2 α- and 2 δ-chains, accounts for only 2% of adult haemoglobin. Haemoglobin F (HbF), found in fetal and early postnatal life, consists of 2 α- and 2 γ-chains. Adult red cells normally contain less than 1% of HbF. In the genetic condition thalassaemia, only one type of chain is expressed normally, the mutant chain being absent or present at much reduced levels. Thus, a molecule may contain 4 α-chains (β-thalassaemia) or 4 β-chains (α-thalassaemia). In haemoglobin S (HbS) of sickle-cell disease, a point mutation in the β-chain gene (valine substituted for glutamine) causes the haemoglobin to polymerize under conditions of low oxygen concentration, thus deforming the red blood cell. In the ABO system, two allelic genes are inherited in simple Mende - lian fashion. Thus the genome may be homozygous and carry the AA complement, the blood group being A, or the BB complement, which gives blood group B, or it may carry neither (OO), producing blood group O. In the heterozygous condition the following combinations can occur: AB (blood group AB), AO (blood group A) and BO (blood group B). The ABO blood group antigens are all membrane glycolipids.antibodies in the donated blood are diluted to insignificant levels. Normally, however, blood is only transfused between persons with cor - responding groups because anomalous antibodies of the ABO system are occasionally found in blood and may cause agglutination or lysis. The anti-ABO agglutinins, unlike those of the Rhesus system, belong to the immunoglobulin M (IgM) class and do not cross the placenta during pregnancy. The Rhesus antigen system is determined by three sets of alleles: namely, Cc, Dd and Ee. The most important clinically is Dd. Inheritance of the Rh factor also obeys simple Mendelian laws; it is therefore pos- sible for a Rhesus-negative mother to bear a Rhesus-positive child. Under these circumstances, fetal Rh antigens can stimulate the produc - tion of anti-Rh antibodies by the mother; as these belong to the IgG class of antibody they are able to cross the placenta. For most of the pregnancy the stroma stops the blood group antibodies from crossing into the fetal circulation. However, immediately prior to birth, the antibodies can cross this barrier and cause destruction of fetal erythro - cytes. In the first such pregnancy little damage usually occurs because anti-Rh antibodies have not been induced, but in subsequent Rh-positive pregnancies massive destruction of fetal red cells may result, causing fetal or neonatal death (haemolytic disease of the newborn). Sensitiza - tion of the maternal immune system can also result from abortion or miscarriage, or occasionally even from amniocentesis, which may intro - duce fetal antigens into the maternal circulation. Treatment is by exchange transfusion of the neonate or, prophylactically, by giving Rh-immune (anti-D) serum to the mother after the first Rh-positive pregnancy, which destroys the fetal Rh antigen in her circulation before sensitization can occur.Individuals with group AB blood lack antibodies to both A and B antigens, and so can be transfused with blood of any group; they are termed universal recipients. Conversely, those with group O, universal donors, can give blood to any recipient, since anti-A and anti-B

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BlOOd, lym PHOI d TISS uES ANd HAE mOPOIESIS 70 SECTION 1 capacity to neutrophils, but are present only in small numbers in normal blood (100–400/ µl). The nucleus has two prominent lobes connected by a thin strand of chromatin. Their cytoplasmic specific granules are uniformly large (0.5 µm) and give the living cell a slightly yellowish colour. The cytoplasm is packed with granules, which are spherical or ellipsoid and membrane-bound. The core of each granule is composed of a lattice of major basic protein, which is responsible for its strong eosinophilic staining properties. The surrounding matrix contains several lysosomal enzymes including acid phosphatase, ribonuclease, phospholipase and a myeloperoxidase unique to eosinophils. Like other leukocytes, eosinophils are motile. When suitably stimu- lated, they are able to pass into the extravascular tissues from the circu - lation. They are typical minor constituents of the dermis, and of the connective tissue components of the bronchial tree, alimentary tract, uterus and vagina. The total lifespan of these cells is a few days, of which some 10 hours is spent in the circulation, and the remainder in the extravascular tissues. Eosinophil numbers rise (eosinophilia) in worm infestations and also in certain allergic disorders, and it is thought that they evolved as a primary defence against parasitic attack. They have surface receptors for IgE that bind to IgE-antigen complexes, triggering phagocytosis and release of granule contents. However, they are only weakly phagocytic and their most important function is the destruction of parasites too large to phagocytose. This antiparasitic effect is mediated via toxic mol - ecules released from their granules (e.g. eosinophil cationic protein and major basic protein). They also release histaminase, which limits the inflammatory consequences of mast cell degranulation. High local con - centrations of eosinophils, e.g. in bronchial asthma and in cutaneous contact sensitivity and allergic eczema, can cause tissue destruction as a consequence of the release of molecules such as collagenase from their granules. Basophil granulocytes Slightly smaller than other granulocytes, basophil granulocytes are 10–14 µm in diameter, and form only 0.5–1% of the total leukocyte population of normal blood, with a count of 25–200/µl. Their distin-guishing feature is the presence of large, conspicuous basophilic gran - ules. The nucleus is somewhat irregular or bilobed, and is usually obscured in stained blood smears by the similar colour of the basophilic granules. The granules are membrane-bound vesicles, which display a variety of crystalline, lamellar and granular inclusions: they contain heparin, histamine and several other inflammatory agents, and closely resemble those of tissue mast cells. Both basophils and mast cells have high-affinity membrane receptors for IgE and are therefore coated with IgE antibody. If this binds to its antigen it triggers degranulation of the cells, producing vasodilation, increased vascular permeability, chemo - tactic stimuli for other granulocytes, and the symptoms of immediate hypersensitivity, e.g. in allergic rhinitis (hay fever). Despite these simi - larities, basophils and mast cells develop as separate lineages in the myeloid series, from haemopoietic stem cells in the bone marrow. Evidence from experimental animal models suggests that they are closely related (see Fig. 4.12) but studies on mast cell disorders in humans indicate that their lineages diverge from a more distant ances - tral progenitor (Kocabas et al 2005). The role of mast cells in the regula - tion of responses to pain is of interest clinically as a therapeutic target (Chatterjea and Martinov 2015). Mononuclear leukocytes Monocytes Monocytes are the largest of the leukocytes (15–20 µm in diameter) but they form only a small proportion of the total population (2–8% with a count of 100–700/ µl of blood). The nucleus, which is euchromatic, is relatively large and irregular, often with a characteristic indentation on one side. The cytoplasm is pale-staining, particulate and typically vacuolated. Near the nuclear indentation it contains a prominent Golgi complex and vesicles. Monocytes are actively phagocytic cells and contain numerous lysosomes. Phagocytosis is triggered by recognition of opsonized material, as described for neutrophils. Monocytes are highly motile and possess a well-developed cytoskeleton. Monocytes express class II MHC antigens and share other similarities to tissue macrophages and dendritic cells. Most monocytes are thought to be in transit via the blood stream from the bone marrow to the peripheral tissues, where they give rise to macrophages and dendritic cells; different monocyte subsets may target inflamed tissues. Like other leukocytes, they pass into extravascular sites through the walls of capil - laries and venules.segmented (multilobed) nuclei. They form the largest proportion of the white blood cells (40–75% in adults, with a normal count of 2500– 7500/µ l) and have a diameter of 12–14 µm. The cells may be spherical in the circulation, but they can flatten and become actively motile within the extracellular matrix of connective tissues. The numerous cytoplasmic granules are heterogeneous in size, shape and content, but all are membrane-bound and contain hydro - lytic and other enzymes. Two major types can be distinguished accord-ing to their developmental origin and contents. Non-specific or primary (azurophilic) granules are formed early in neutrophil matura - tion. They are relatively large (0.5 µm) spheroidal lysosomes contain - ing myeloperoxidase, acid phosphatase, elastase and several other enzymes. Specific or secondary granules are formed later, and occur in a wide range of shapes including spheres, ellipsoids and rods. These contain strong bacteriocidal components including alkaline phos- phatase, lactoferrin and collagenase, none of which is found in primary granules. Conversely, secondary granules lack peroxidase and acid phosphatase. Some enzymes, e.g. lysozyme, are present in both types of granule. In mature neutrophils the nucleus is characteristically multilobed with up to six (usually three or four) segments joined by narrow nuclear strands; this is known as the segmented stage. Less mature cells have fewer lobes. The earliest to be released under normal conditions are juveniles (band or stab cells), in which the nucleus is an unsegmented crescent or band. In certain clinical conditions, even earlier stages in neutrophil formation, when cells display indented or rounded nuclei (metamyelocytes or myelocytes) may be released from the bone marrow. In mature cells the edges of the nuclear lobes are often irregular. In females 3% of the nuclei of neutrophils show a conspicuous ‘drum - stick’ formation, which represents the sex chromatin of the inactive X chromosome (Barr body). Neutrophil cytoplasm contains few mito - chondria but abundant cytoskeletal elements, including actin filaments, microtubules and their associated proteins, all characteristic of highly motile cells. Neutrophils are important in the defence of the body against micro- organisms. They can phagocytose microbes and small particles in the circulation and, after extravasation, they carry out similar activities in other tissues. They function effectively in relatively anaerobic condi - tions, relying largely on glycolytic metabolism, and they fulfil an impor - tant role in the acute inflammatory phase of tissue injury, responding to chemotaxins released by damaged tissue. Phagocytosis of cellular debris or invading microorganisms is followed by fusion of the phago - cytic vacuole with granules, which results in bacterial killing and diges - tion. Actively phagocytic neutrophils are able to reduce oxygen enzymatically to form reactive oxygen species including superoxide radicals and hydrogen peroxide, which enhance bacterial destruction probably by activation of some of the granule contents (Segal 2005, Nathan 2006). Neutrophils can also produce neutrophil extracellular traps (NETs), which are web-like structures composed of DNA and proteolytic enzymes that can trap bacteria and kill them (Kaplan and Radic 2012). Phagocytosis is greatly facilitated by circulating antibodies to mol - ecules such as bacterial antigens, which the body has previously encountered. Antibodies coat the antigenic target and bind the plasma complement protein, C1, to their non-variable Fc regions. This activates the complement cascade, which involves some 20 plasma proteins synthesized mainly in the liver, and completes the process of opsoniza - tion. The complement cascade involves the sequential cleavage of the complement proteins into a large fragment, which generally binds to the antigenic surface, and a small bioactive fragment, which is released. The final step is the recognition of complement by receptors on the surfaces of neutrophils (and macrophages), which promotes phagocy - tosis of the organism. Neutrophils are short-lived; they spend some 6–7 hours circulating in the blood and a few days in connective tissues. The number of cir - culating neutrophils varies, and often rises during episodes of acute bacterial infection. They die after carrying out their phagocytic role; dead neutrophils, bacteria, tissue debris (including tissue damaged by neutrophil enzymes and toxins) and interstitial fluid form the charac - teristic, greenish-yellow pus of infected tissue. The colour is derived from the natural colour of neutrophil myeloperoxidase. Granules may also be released inappropriately from neutrophils. Their enzymes are implicated in various pathological conditions, e.g. rheumatoid arthritis, where tissue destruction and chronic inflamma - tion occur. Eosinophil granulocytes Eosinophil granulocytes (eosinophils; for a review, see Rothenberg and Hogan (2006)) are similar in size (12–15 µm), shape and motile

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Cells of peripheral blood 71 CHAPTER 4 germinal centres in the lymphoid tissues. Following this, some B cells differentiate into large basophilic (RNA-rich) plasma cells, either within or outside the lymphoid tissues. Plasma cells produce antibodies in their extensive rough endoplasmic reticulum (Fig. 4.6) and secrete them into the adjacent tissues. They have a prominent pale-staining Golgi complex adjacent to an eccentrically placed nucleus, typically with peripheral blocks of condensed heterochromatin resembling the numerals of a clock (clock-faced nucleus) (see Fig. 4.12). Other germi - nal centre B cells develop into long-lived memory cells capable of responding to their specific antigens not only with a more rapid and higher antibody output, but also with an increased antibody affinity compared with the primary response. Antibodies are immunoglobulins, grouped into five classes accord - ing to their heavy polypeptide chain. Immunoglobulin G (IgG) forms the bulk of circulating antibodies. Immunoglobulin M (IgM) is nor - mally synthesized early in immune responses. Immunoglobulin A (IgA) is present in breast milk, tears, saliva and other secretions of the ali - mentary tract, coupled to a secretory piece (a 70 kDa protein) that is synthesized by the epithelial cells. This protects the immunoglobulin from proteolytic degradation and is part of the process by which the molecule is transported across the epithelium; IgA thus contributes to mucosal immunity. IgA deficiency is relatively common, particularly in Lymphocytes Lymphocytes (Fig. 4.4; see Figs 4.6, 4.12) are the second most numer - ous type of leukocyte in adulthood, forming 20–30% of the total popu - lation (1500–2700/µl of blood). In young children they are the most numerous blood leukocyte. Most circulating lymphocytes are small, 6–8 µm in diameter; a few are medium-sized and have an increased cytoplasmic volume, often in response to antigenic stimulation. Occa - sionally, cells up to 16 µm are seen in peripheral blood. Lymphocytes, like other leukocytes, are found in extravascular tissues (including lym - phoid tissue); however, they are the only white blood cells that return to the circulation. The lifespan of lymphocytes ranges from a few days (short-lived) to many years (long-lived). Long-lived lymphocytes are necessary for the maintenance of immunological memory. Blood lymphocytes are a heterogeneous collection mainly of B and T cells, and consist of different subsets and different stages of activity and maturity. About 85% of all circulating lymphocytes in normal blood are T cells. Primary immunodeficiency diseases can result from molecular defects in T and B lymphocytes (reviewed in Cunningham- Rundles and Ponda (2005)). Included with the lymphocytes, but prob - ably constituting a separate lineage subset, are the natural killer (NK) cells. NK cells most closely resemble large T cells morphologically. Small lymphocytes (both B and T cells) contain a rounded, densely staining nucleus that is surrounded by a very narrow rim of cytoplasm, barely visible in the light microscope. In the electron microscope (see Fig. 4.4), few cytoplasmic organelles can be seen apart from a small number of mitochondria, single ribosomes, sparse profiles of endoplas- mic reticulum and occasional lysosomes; these features indicate a low metabolic rate and a quiescent phenotype. However, these cells become motile when they contact solid surfaces, and can pass between endothe - lial cells to exit from, or re-enter, the vascular system. They migrate extensively within various tissues, including epithelia ( Fig. 4.5). Larger lymphocytes include T and B cells that are functionally acti - vated or proliferating after stimulation by antigen, and NK cells. They contain a nucleus, which is, at least in part, euchromatic; a basophilic cytoplasm, which may appear granular; and numerous polyribosome clusters, consistent with active protein synthesis. The ultrastructural appearance of these cells varies according to their class and is described below. B cells B cells and the plasma cells that develop from them synthesize and secrete antibodies that can specifically recognize and neutralize foreign (non-self) macromolecules (antigens), and can direct various non-lymphocytic cells (e.g. neutrophils, macrophages and dendritic cells) to phagocytose pathogens. B cells differentiate from haemopoietic stem cells in the bone marrow. After deletion of autoreactive cells, the selected B lymphocytes then leave the bone marrow and migrate to peripheral lymphoid sites (e.g. lymph nodes). Here, following stimulation by antigen, they undergo further proliferation and selection, forming Fig. 4.4 A small, resting lymphocyte in human peripheral blood. The nuclear:cytoplasmic ratio is high and the cytoplasm contains few organelles, indicative of its quiescent state. (Courtesy of Dr Bart Wagner, Histopathology Department, Sheffield Teaching Hospitals, UK.) Fig. 4.5 Tubular glands in the appendix, showing intraepithelial lymphocytes (short arrows). A lymphocyte in anaphase is indicated (long arrow). Fig. 4.6 A mature B cell (plasma cell) in human connective tissue. The abundant rough endoplasmic reticulum is typical of a cell actively synthesizing secretory protein, in this case immunoglobulin. The cell to the left is a fibroblast. (Courtesy of Dr Bart Wagner, Histopathology Department, Sheffield Teaching Hospitals, UK.)

Gray's Anatomy: 41st Edition

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