document_idx
int64 0
4.43k
| text
stringlengths 3
1.35k
| page_idx
int64 20
2.25k
| document_name
stringclasses 1
value | file_path
stringclasses 1
value | file_url
stringclasses 1
value | loader_name
stringclasses 2
values | source
stringclasses 1
value |
|---|---|---|---|---|---|---|---|
19 | 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. | 42 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
20 | 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 | 43 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
20 | 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 | 43 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
20 | 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- | 43 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
20 | 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 | 43 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
20 | 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 | 43 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
21 | 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 | 44 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
21 | 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 | 44 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
21 | 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 | 44 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
21 | 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 | 44 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
21 | 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 | 44 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
21 | 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 | 44 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
22 | 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 - | 45 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
22 | 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. | 45 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
23 | 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 | 46 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
23 | 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 | 46 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
23 | 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. | 46 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
23 | 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 | 46 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
23 | 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 | 46 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
23 | 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 | 46 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
23 | 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.) | 46 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
23 | 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. | 46 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
24 | 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. | 47 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
24 | 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 | 47 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
24 | (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). | 47 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
25 | 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 | 48 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
25 | 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 | 48 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
25 | 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 | 48 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
25 | 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. | 48 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
25 | 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 - | 48 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
25 | 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 | 48 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
25 | 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 | 48 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
25 | 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 - | 48 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
25 | 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 | 48 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
26 | 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. | 49 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
27 | 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, | 50 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
27 | 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 | 50 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
27 | 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 | 50 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
27 | 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 - | 50 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
27 | 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, | 50 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
27 | 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. | 50 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
27 | 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 - | 50 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
27 | 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 - | 50 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
27 | 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 | 50 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
27 | 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 - | 50 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
28 | 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. | 51 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
29 | 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 | 52 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
29 | 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 - | 52 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
29 | 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 | 52 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
29 | 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 | 52 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
29 | 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 - | 52 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
29 | 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 | 52 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
29 | 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 | 52 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
29 | 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 | 52 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
29 | 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 | 52 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
30 | 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 | 53 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
30 | 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). | 53 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
30 | 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 | 53 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
30 | (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 | 53 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
30 | 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 | 53 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
30 | 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) | 53 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
30 | 19–20 (F) Shortest metacentrics
21–22 + Y (G) Short acrocentrics; 21, 22 with satellites, Y without | 53 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
31 | 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. | 54 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
32 | 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 | 55 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
32 | 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 | 55 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
32 | 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 - | 55 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
32 | 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 - | 55 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
32 | 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 | 55 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
32 | 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 - | 55 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
32 | 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 | 55 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
32 | (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 | 55 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
32 | 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 | 55 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
32 | G1Checkpoint 1Checkpoint 2 | 55 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
33 | 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. | 56 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
34 | 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). | 57 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
34 | 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 | 57 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
34 | 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. | 57 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
34 | 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 - | 57 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
34 | 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 | 57 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
34 | 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 | 57 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
35 | 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. | 58 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
35 | 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, | 58 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
35 | 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 | 58 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
35 | 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 | 58 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
36 | Cell polarity and domains
21
CHaPTER 1
equatorial plane of the spindle. The centromeres of each pair of sister
chromatids function as a single unit, facing a single spindle pole.
Homologous chromosomes are pulled towards opposite spindle poles,
but are held paired at the spindle midzone by chiasmata. Errors in
chromosome segregation (known as non-disjunction) lead to the pro-
duction of aneuploid progeny. Most human aneuploid embryos are
non-viable and this is the major cause of fetal loss (spontaneous abor -
tion), particularly during the first trimester of pregnancy in humans. The most common form of viable aneuploid progeny in humans is
Down’s syndrome (trisomy for chromosome 21), which exhibits a dra-
matic increase with maternal age.
Anaphase and telophase I
Anaphase I of meiosis begins with the release of cohesion between the
arms of sister chromatids, much as it does during mitosis. As position -
ing of bivalent pairs is random, assortment of maternal and paternal chromosomes in each telophase nucleus is also random. Critically, | 59 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
36 | sister centromeres, and thus chromatids, do not separate during ana-
phase I.
During meiosis I, cytoplasmic division occurs by specialized mecha -
nisms. In females, the division is highly asymmetric, producing one egg
and one tiny cell known as a polar body. In males, the process results
in production of spermatocytes that remain joined by small cytoplas -
mic bridges.
meiosis II
Meiosis II commences after only a short interval during which no DNA
synthesis occurs. The centromeres of sister chromatids remain paired,
but rotate so that each one can face an opposite spindle pole. Onset of
anaphase II is triggered by loss of cohesion between the centromeres,
as it is in mitosis. This second division is more like mitosis, in that
chromatids separate during anaphase, but, unlike mitosis, the separat -
ing chromatids are genetically different (the result of genetic recombi -
nation). Cytoplasmic division also occurs and thus, in the male, four
haploid cells, interconnected by cytoplasmic bridges, result from
meiosis I and II.
CELL POLARITY AND DOMAINS | 59 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
36 | Epithelia are organized into sheets or glandular structures with very
different environments on either side. These cells actively transfer mac-
romolecules and ions between the two surfaces and are thus polarized
in structure and function. In polarized cells, particularly in epithelia,
the cell is generally subdivided into domains that reflect the polariza -
tion of activities within it. The free surface, e.g. that facing the intestinal lumen or airway, is the apical surface, and its adjacent cytoplasm is the
apical cell domain. This is where the cell interfaces with a specific body
compartment (or, in the case of the epidermis, with the outside world).
The apical surface is specialized to act as a barrier, restricting access of
substances from this compartment to the rest of the body. Specific
components are selectively absorbed from, or added to, the external
compartment by the active processes, respectively, of active transport
and endocytosis inwardly or exocytosis and secretion outwardly.
The apical surface is often covered with small protrusions of the cell surface, microvilli, which increase the surface area, particularly for
absorption. | 59 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
36 | The surface of the cell opposite to the apical surface is the basal
surface, with its associated basolateral cell domain. In a single-layered
epithelium, this surface faces the basal lamina. The remaining surfaces
are known as the lateral cell surfaces. In many instances, the lateral and
basal surfaces perform similar functions and the cellular domain is
termed the basolateral domain. Cells actively transport substances, such
as digested nutrients from the intestinal lumen or endocrine secretions,
across their basal (or basolateral) surfaces into the subjacent connective
tissue matrix and the blood capillaries within it. Dissolved non-polar
gases (oxygen and carbon dioxide) diffuse freely between the cell and
the blood stream across the basolateral surface. Apical and basolateral
surfaces are separated by a tight intercellular seal, the tight junction
(occluding junction, zonula adherens), which prevents the passage of
even small ions through the space between adjacent cells and thus
maintains the difference between environments on either side of the
epithelium.
Cell surface apical differentiations | 59 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
36 | The surfaces of many different types of cell are specialized to form structures that project from the surface. These projections may permit meiosis I
Prophase I
Meiotic prophase I is a long and complex phase that differs consider -
ably from mitotic prophase and is customarily divided into five sub -
stages, called leptotene, zygotene, pachytene, diplotene and diakinesis.
There are three distinctive features of male meiotic prophase that are
not seen during mitotic prophase: the pairing, or synapse, of homolo -
gous chromosomes of paternal and maternal origin to form bivalent structures; the organization of nucleoli by autosomal bivalents; and
significant non-ribosomal RNA synthesis by autosomal bivalents (in
contrast to the transcriptional inactivity of the XY chromosomal pair)
(see Tres 2005). In the female, meiotic prophase I starts during fetal
gonadogenesis, is arrested at the diplotene stage and resumes at puberty. In the male, meiosis starts at puberty.
Leptotene stage During leptotene, homologous chromosomes | 59 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
36 | (maternal and paternal copies of the same chromosome), replicated in
a preceding S phase and each consisting of sister chromatids joined at
the centromere (see above), locate one another within the nucleus, and
the process of genetic recombination is initiated. Cytologically, chro -
mosomes begin to condense, appearing as individual threads that are attached via their telomeres to the nuclear envelope. They often show
characteristic beading throughout their length.
Zygotene stage During zygotene, the homologous chromosomes
initiate pairing or synapsis, during which they become intimately asso -
ciated with one another. Synapsis may begin near the telomeres at the inner surface of the nuclear membrane, and during this stage the tel -
omeres often cluster to one side of the nucleus (a stage known as the bouquet because the chromosomes resemble a bouquet of flowers). The
pairs of synapsed homologues, also known as bivalents, are linked
together by a tripartite ribbon, the synaptonemal complex, which con -
sists of two lateral dense elements and a central, less dense, linear element. | 59 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
36 | The sex chromosomes also start to synapse during zygotene. In
males, with distinct X and Y chromosomes, synapsis involves a region
of shared DNA sequence known as the pseudoautosomal region. The
XY bivalent adopts a special condensed structure, known as the sex
vesicle, which becomes associated later at pachytene with migratory
nucleolar masses originating in the autosomal bivalents.
Chromosome behaviour in meiosis is intimately linked with the
process of genetic recombination. This begins during leptotene, as
homologous chromosomes first locate one another at a distance. Syn -
apsis, stabilized by the synaptonemal complex, facilitates recombina -
tion, as sites of genetic exchange are turned into specialized structures
known as chiasmata, which are topological crossing-over points that
hold homologous chromosomes together.
Pachytene stage When synapsis is complete for all chromosomes,
the cell is said to be in pachytene. Each bivalent looks like a single thick structure, but is actually two pairs of sister chromatids held together by
the synaptonemal complex. Genetic recombination between non-sister | 59 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
36 | chromatids is completed at this point, with sites where it has occurred
(usually one per chromosome arm) appearing as recombination
nodules in the centre of the synaptonemal complex.
Diplotene stage During diplotene, the synaptonemal complex disas -
sembles and pairs of homologous chromosomes, now much shortened, separate, except where crossing over has occurred (chiasmata). This
process is called disjunction. At least one chiasma forms between each
homologous pair, exchanging maternal and paternal sequences; up to
five have been observed. In the ovaries, primary oocytes become diplo -
tene by the fifth month in utero and each remains at this stage until the
period before ovulation (up to 50 years).
Diakinesis Diakinesis is the prometaphase of the first meiotic divi-
sion. The chromosomes, still as bivalents, become even shorter and
thicker. They gradually attach to the spindle and become aligned at a
metaphase plate. In eggs, the spindle forms without centrosomes.
Microtubules first nucleate and are stabilized near the chromosomes; | 59 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
36 | the action of various motor molecules eventually sorts them into a
bipolar spindle. Perhaps surprisingly, this spindle is as efficient a
machine for chromosome segregation as the spindle of mitotic cells with centrosomes at the poles.
Metaphase I
Metaphase I resembles mitotic metaphase, except that the bodies attach -
ing to the spindle microtubules are bivalents, not single chromosomes. These become arranged so that the homologous pairs occupy the | 59 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
37 | BaSIC STR uCTuRE aNd fu NCTION Of CEllS
22 SECTION 1
its distal region, called the transition zone. The continued elongation
of the cilium requires the import and intraciliary transport of tubulin
dimers to the distal tip by bidirectional motor-driven proteins of the
intraflagellar transport complex.
The constant length of cilia is maintained by a steady-state balance
between tubulin turnover and addition of new tubulin dimers at the
ciliary tip.
Several filamentous structures are associated with the 9 + 2 doublet
microtubule of the axoneme in the cilium or flagellum shaft, e.g. radial
spokes extend inwards from the outer doublet microtubules towards
the central pair, surrounded by an inner sheath (see Fig. 1.17). The outer
doublet microtubules bear two rows of tangential dynein arms attached to the complete A subfibre of the doublet (consisting of 13 protofila - | 60 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
37 | ments), which point towards the incomplete B subfibre of the adjacent doublet (consisting of 10–1 1 protofilaments). Adjacent doublets are
also linked by thin nexin filaments. Tektins are scaffolding filamentous
proteins extending along the axonemal microtubules.
In motile cilia, arrays of dynein arms with ATPase activity cause outer
microtubule doublets to move past one another, resulting in a large-
scale bending motion. Microtubules do not change in length. Move -
ments of cilia and flagella are broadly similar. In addition to the axoneme, spermatozoan flagella have outer dense fibres and a fibrous
sheath surrounding the axoneme. Flagella move by rapid undulation,
which passes from the attached to the free end. In human spermatozoa,
there is an additional helical component to this motion. In cilia, the
beating is planar but asymmetric. In the effective stroke, the cilium
remains stiff except at the base, where it bends to produce an oar-like
stroke. The recovery stroke follows, during which the bend passes from | 60 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
37 | base to tip, returning the cilium to its initial position for the next cycle.
The activity of groups of cilia is usually coordinated so that the bending
of one is rapidly followed by the bending of the next and so on, movement of the cell itself (flagella), or of fluids across the apical cell
surface (cilia), or increase the surface area available for absorption
(microvilli). Infoldings of the basolateral plasma membrane also
increase the area for transport across this surface of the cell. In most
non-dividing epithelial cells, the centriole-derived basal body gives rise
to a non-motile primary cilium, which has an important mechanosen -
sory role.
Cilia and flagella
Cilia and flagella are motile, hair-like projections of the cell surface, which create currents in the surrounding fluid or movements of the cell
to which they are attached, or both. There are two categories of cilia:
single non-motile primary cilia and multiple motile cilia. Primary cilia
are immotile but can detect physical and biochemical signals. Motile
cilia are present in large numbers on the apical epithelial domain of | 60 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
37 | the upper respiratory tract and oviducts, and beat in a wave-like motion
to generate fluid movement. Cilia also occur, in modified form, at the
dendritic endings of olfactory receptor cells, vestibular hair cells (kino -
cilium), and the photoreceptor rods and cones of the retina. Flagella, with a primary function in cell locomotion, are found on single-cell
eukaryotes and in spermatozoa, which each possess a single flagellum
70 µm long.
A cilium or flagellum consists of a shaft (0.25 µm diameter) consti-
tuting most of its length, a tapering tip and a basal body at its base,
which lies within the surface cytoplasm of the cell ( Fig. 1.17). Other
than at its base, the entire structure of the cilium is covered by plasma membrane. The core of the cilium is the axoneme, a cylinder of nine
microtubule doublets that surrounds a central pair of single microtu -
bules (see Fig. 1.17). Ciliogenesis of primary cilia and motile cilia | 60 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
37 | involves distinct steps. A centriole-derived basal body migrates to the
apical cell domain and axonemal microtubule doublets emerge from
Fig . 1 .17 A, The structure of a cilium shown in longitudinal (left) and transverse (right) section . A and B are subfibres of the peripheral microtubule
doublets (see text); the basal body is structurally similar to a centriole, but with microtubule triplets . B, The apical region of respiratory epithelial cells,
showing the proximal parts of three cilia sectioned longitudinally, anchored into the cytoplasm by basal bodies (BB) . Other cilia project out of the plane
of section and are cut transversely, showing the ‘9 + 2’ arrangement of microtubules . (B, With permission from Young B, Heath JW . Wheater’s Functional
Histology . 4th ed . Edinburgh: Elsevier, Churchill Livingstone; 2000 .)Inner sheath
Central
microtubulesDynein ‘arms’
RootletA
Microtubule
doubletsNexin-linking
protein | 60 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
37 | Radial spokeAB
Tubulin subunits
Microtubule
tripletsPlasma membrane
Basal body
B
BBBB | 60 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |
38 | Basic structure and function of cells
22.e1
CHaPTER 1
As indicated on page 15, the IFT-B protein complex participates in
intraciliary/intraflagellar anterograde transport of cargoes, a step essen-
tial for the assembly and maintenance of cilia and flagella; the IFT-A
protein complex is required for retrograde transport of cargoes to the
cell body for turnover. The movement of IFT proteins along microtu -
bules is catalysed by kinesin-2 (towards the ciliary tip; anterograde direction) and cytoplasmic dynein-2 motor proteins (towards the cell
body; retrograde direction). A cargo includes axonemal components,
ciliary/flagellar membrane proteins (including the BBSome) and ciliary
signal transduction proteins. | 61 | Gray's Anatomy: 41st Edition | grays_anatomy.pdf | https://archive.org/download/GraysAnatomy41E2015PDF/Gray%27s%20Anatomy%2041E%202015.pdf | PyPDF2TextLoader | https://archive.org/details/GraysAnatomy41E2015PDF |