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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

Gray's Anatomy: 41st Edition

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