The nucleus contains the DNA blueprint for the cell and machinery to replicate DNA and synthesize RNA. It regulates transport between the nuclear and cytoplasmic compartments, and contains heterochromatin and euchromatin. The nuclear envelope is a double membrane with nuclear pores that regulate transport. It surrounds the nucleolus, which synthesizes ribosomal components, and the chromatin, which condenses during cell division.

1. THE CELL NUCLEUS
Department Of General Histology

2. Introduction
 The nucleus contains a blueprint for all cell
structures and activities encoded in the DNA of
the chromosomes. It also contains the molecular
machinery to replicate its DNA and to synthesize
and process all types of RNA. Macromolecular
transfer between the nuclear and cytoplasmic
compartments is regulated. Because functional
ribosomes do not occur in the nucleus, no
proteins are produced there. The numerous
protein molecules needed for the activities of the
nucleus are imported from the cytoplasm.

3. Nuclei of large, active
cells
Liver cells (hepatocytes) have large,
well-stained nuclei located in the
center of the cytoplasm. One or more
nucleoli are seen inside each nucleus,
indicating intense protein synthesis by
these cells. Most of the chromatin is
light-staining or euchromatic, with small
areas of more darkly stained
heterochromatin scattered throughout
the nucleus and just inside the nuclear
envelope. This superficial
heterochromatin allows the boundary of
the organelle to be seen more easily by
light microscopy. One cell here has two
nuclei, which is fairly common in the
liver. X500. Pararosaniline–toluidine
blue.

4. Structural components of the
nucleus.
(a): TEM of a typical cell
nucleus clearly shows the
electron-dense
heterochromatin (HC) and
the more diffuse euchromatin
(EC). The arrows indicate the
nucleolus-associated
heterochromatin around the
nucleolus (NU). Arrowheads
indicate areas where the
perinuclear space between
the two membranes of the
nuclear envelope is clearly
seen. Just inside the nuclear
envelope is a thin electron-
dense region containing the
nuclear lamina and more
heterochromatin.

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6. (b): Schematic representation of a cell
nucleus shows that the nuclear
envelope is made of two membranes
separated by the perinuclear space.
The outer membrane has ribosomes
bound to it and is continuous with the
ER. The two membranes fuse at many
places to form nuclear pores.
Heterochromatin clumps (HC) are
associated with the meshwork of the
nuclear lamina just inside the nuclear
envelope, whereas the euchromatin
(EC) appears dispersed in the interior
of the nucleus. The nucleolus contains
distinct regions called the pars
granulosa (G) and the pars fibrosa (F).

7. Relationship of nuclear
envelope to the rough ER

8. Nuclear lamina
The nuclear lamina is formed from a
class of intermediate filaments
proteins, the lamins, which assemble as
a lattice adjacent to the inner nuclear
membrane. When the nuclear envelope
disperses during early prophase of cell
division, at least some lamin proteins
remain attached to the membrane
fragments and reassembly of the
nuclear lamina immediately after cell
division facilitates re-formation of the
nuclear envelopes of the two new
nuclei. The nuclear lamina also contains
binding sites for chromatin, helping to
organize this material in the nucleus.
Chromatin is not present at the
openings through the nuclear envelope
called nuclear pore complexes.

9. Nuclear pores
•(a): Section through the nuclear
envelope and the two-membrane
structure of the nuclear envelope
clearly. The electron-dense proteins
that make up the nuclear pore
complexes can also be seen (arrows).
Immediately beneath the nuclear
envelope is the nuclear lamina and
heterochromatin, material that is not
present however at the nuclear
pores.
•(b): Tangential section through a
nuclear envelope shows the electron-
dense nuclear pore complexes
(arrows) and the electron-lucent
patches in the peripheral
heterochromatin which represent the
areas just inside the pores.

10. Cryofracture of nuclear envelop showing nuclear pores
Electron micrograph obtained by freeze-fracture of an intestinal cell shows the two components of the
nuclear envelope and the nuclear pores. The fracture plane occurs partly between the two nuclear envelope
membranes (left) but mostly just inside the envelope with the chromatin falling away. The size and distribution
of the nuclear pore complexes are clearly seen. The same nuclear pore complexes can mediate both the
import and export of macromolecules between the nucleus and cytoplasm using tightly controlled processes
in each direction.

11. Components of a nucleosome
Nucleosome is a structure that produces the initial organization of free double-stranded DNA into chromatin.
Each nucleosome has an octomeric core complex made up of four types of histones, two copies each of H2A,
H2B, H3, and H4. Around this core is wound DNA approximately 150 base pairs in length. One H1 histone is
located outside the DNA on the surface of each nucleosome. DNA associated with nucleosomes in vivo thus
resembles a long string of beads. Nucleosomes are very dynamic structures, with H1 loosening and DNA
unwrapping at least once every second to allow other proteins, including transcription factors and enzymes,
access to the DNA.

12. Sex chromatin
Either X chromosome in cells from females can undergo inactivation and clumping to form heterochromatic sex
chromatin. Morphologic features of sex chromatin can be seen in human female epithelial cells lining the mouth
and neutrophils. Left: In the oral epithelial cells, heterochromatic sex chromatin appears as a small granule
adhering to the nuclear envelope. These superficial buccal cells lining the cheeks are frequently used to study
sex chromatin or as a very convenient source of nucleated cells for DNA analyses. Right: In neutrophils,
chromatin often has the shape of a drumstick projecting from the multilobed nucleus that is unique to these
cells. The genetically inactive, heterochromatic X chromosome comprising the sex chromatin is sometimes
called a Barr body, after the cytologist who first discovered it in the cells of females.

13. Several orders of chromatin packing are believed to
occur during condensation of chromatin during mitotic
prophase, although the protein associations involved
at each stage are not well understood. Genetic
activity is almost completely shut down during this
process and histones are chemically modified in
various ways. The top drawing shows the 2-nm DNA
double helix, followed by the association of DNA with
histones to form 11-nm filaments of nucleosomes
connected by the DNA ("beads on a string").
Nucleosomes on the DNA then interact in a manner
not well understood to form a more compact 30-nm
fiber. Through further condensation, filaments with
diameters of 300 nm and 700 nm are formed. The
highly folded loops of chromatin at these stages are
stabilized by interactions with protein complexes
made of condensins which eventually make up a
central framework at the long axis of each chromatid.
The bottom drawing shows a metaphase chromosome,
which exhibits the maximum packing of DNA. The
chromosome consists of two chromatids held
together at a narrow point called the centromere.

14. Karyotyping
Human karyotype preparations are made by staining and then photographing the
chromosomes of cells disrupted after mitotic arrest with colchicine. Nuclei are chosen for
analysis in which the individual chromosomes are maximally condensed. The individual
chromosomes are cut from the photograph and pasted together in various ways for study.
With certain stains each chromosome has a particular pattern of banding that facilitates
its identification and shows the relationship of the banding pattern to genetic anomalies.
The 22 pairs of autosomes are numbered in order of decreasing size; the pair of X and Y
chromosomes differ in both size and morphology

15. Nucleoli
Primary oocytes are very large cells with very large round euchromatic nuclei. The cells
are actively increasing in volume, synthesizing much protein and many ribosomes, and
each nucleus has one well-developed, intensely basophilic nucleolus. The strong
basophilia reflects the high concentration of rRNA being processes in this small region
of nucleoplasm. Other cells may each have one large nucleolus or a few smaller
nucleoli. All are involved in transcription and processing of rRNA. Primary oocytes
arrest for a prolonged period during prophase of the first meiotic division, when the
chromosomes have already begun to condense. Parts of the condensed chromosomes
are seen as the stained material in the sectioned nuclei shown here. Meiosis in oocytes
will proceed just before they are ovulated

16. Regions within a nucleolus
Different regions of the nucleolus can often be
seen in sections of cell nuclei examined by
TEM. The major parts of the nucleolus
identified in this way are one or more pale-
staining regions containing nucleolar
organizer (NO) DNA—sequences of bases
coding for rRNA. In the human genome, five
pairs of chromosomes contain nucleolar
organizers. Closely associated with the
nucleolar organizers are densely packed 5- to
10-nm ribonucleoprotein fibers of the pars
fibrosa (PF), which consists of primary rRNA
transcripts. The pars granulose (PG) consists
of 15- to 20-nm granules that represent
maturing ribosomal subunits. Proteins,
synthesized in the cytoplasm, become
associated with rRNAs in the nucleolus. The
resulting ribosomal subunits are then exported
to the cytoplasm. A small amount of
heterochromatic nucleolus-associated
chromatin (NAC) is also sometimes part of the
nucleolus, but its functional significance is
unknown.

17. Cell Division

18.  Cell division, or mitosis (Gr. mitos, a thread), can
be observed with the light microscope. During
this process, the parent cell divides, and each of
the daughter cells receives a chromosomal set
identical to that of the parent cell. Essentially, a
longitudinal duplication of the chromosomes
takes place, and these chromosomes are
distributed to the daughter cells. The period
between mitoses is called interphase, during
which the DNA is replicated and the nucleus
appears as it is most commonly seen in
histological preparations. The process of mitosis
is subdivided into four phases

19. Phases of mitosis

20.  Chromosomal changes during mitosis are easily seen and most
commonly studied in large cultured cells or in the large cells in
the very early embryos of invertebrates or primitive
vertebrates after sectioning. Shown here are cells in sections of
a fish blastodisc. a. During the relatively long prophase the
centrosomes move to opposite poles, the nuclear envelope
fragments, and chromosomes condense and become visible.
Having undergone DNA replication, each chromosome
consists of two chromatids joined at their centromere regions
by a kinetochore protein complex. b. At the short metaphase
the chromosomes have become aligned at the equatorial plate
as a result of their attachments to the dynamic microtubules
which run from the kinetochores to the centrosomes. c. During
anaphase the kinetochores come apart and the chromatids
(now called chromosomes themselves) are pulled on
microtubules toward the two centrosomes. d. In telophase the
cell pinches in two by constriction of bundled actin filaments in
the cell cortex and the chromosomes decondense,
transcription resumes, nucleoli reappear, and the nuclear
lamina and nuclear envelopes reassemble

21. In the lining of the small intestine, many
mitotic transit amplifying cells, progeny of
nearby stem cells that are not yet fully
differentiated, can be found in the area above
the most basal region of the intestinal crypts.
Condensed chromosomes of cells in late
anaphase and telophase phase can be
distinguished

22. Metaphase cells in a gland of
proliferating uterine endometrium

23. Telophase cells in the esophagus lining.

24. Metaphase in the basal layer of epidermis.
Mitotic figures are normally difficult to identify
in most animal tissues, both because they are
rare and because the various cell shapes and
locations seldom allow specific phases of
mitosis to be seen clearly. Most commonly,
mitotic figures in organs appear simply as
nuclei with clumped, darkly stained
chromatin. X400. H&E.

31. Mitotic cells in adult
tissues
(a): In the lining of the small intestine, many
mitotic transit amplifying cells, progeny of
nearby stem cells that are not yet fully
differentiated, can be found in the area above
the most basal region of the intestinal crypts.
Condensed chromosomes of cells in late
anaphase and telophase phase can be
distinguished.

32. (b): Metaphase cells in a gland of proliferating
uterine endometrium.

33. (c):Telophase cells in the esophagus lining.

34. (d): Metaphase in the basal layer of epidermis.
Mitotic figures are normally difficult to identify
in most animal tissues, both because they are
rare and because the various cell shapes and
locations seldom allow specific phases of
mitosis to be seen clearly. Most commonly,
mitotic figures in organs appear simply as
nuclei with clumped, darkly stained
chromatin.

35. The Cell Cycle

36. The cell cycle

37. Control of the cell cycle
One factor determining the time a cell spends in G1 is
the cell's state of differentiation, or how much time it
spends expressing gene products specific to its cell
type before resuming DNA replication. Differentiating
cells in growing tissues may have very long G1 periods
and such cells are often said to be "in a G0 phase" of
the cell cycle. From this phase many differentiated
cells can return to the cycle, but some stay in G0 for a
long time or even for their entire lifetime. Entry into
each phase of the cell cycle is controlled by proteins
called cyclins and cyclin-dependent kinases which
phosphorylate/activate many proteins needed for
phase-specific functions. Cyclin activity produces an
important restriction point (R) late in G1 and a similar
G2/M checkpoint which are important for the
maintenance of chromosome stability and cell viability.
These control points stop the cycle under conditions
unfavorable to the cell and help insure that neither the
DNA replication nor the mitotic phases occurs
prematurely. For example, at the G2/M checkpoint the
cell pauses while enzymes insure that all DNA has
been replicated properly.

38. Stem cells
In rapidly growing adult tissues and
perhaps in other tissues there are
slowly dividing populations of stem
cells. Stem cells divide asymmetrically,
producing one cell that remains as a
stem cell and another which becomes
committed to a differentiative pathway
but divides a few more times at a
more rapid rate. Such cells have been
termed "transit amplifying cells," each
of which eventually stops dividing and
becomes fully differentiated.

39. Mitosis
Mitosis and meiosis share many aspects of chromatin condensation and separation,
but differ in various key ways. As chromosomal condensation begins in meiosis, the
two homologous maternal and paternal chromosomes physically align in synapsis
and regions are exchanged during crossing over or recombination.

40. Meiosis
This is followed by two meiotic divisions with no intervening S phase. Mitosis
produces two diploid cells which are the same genetically. Meiosis with its two
successive cell divisions produces four haploid cells. During meiotic crossing over,
new combinations of genes arise so that every haploid cell is genetically unique.

41. Apoptosis
 Less evident, but no less important than cell proliferation for
body functions, is the process of cell suicide or programmed cell
death called apoptosis (Gr. apo, off + ptosis, a falling). Apoptosis
is a highly regulated cellular activity that occurs rapidly and
produces small membrane-enclosed apoptotic bodies, which
quickly undergo phagocytosis by neighboring cells or
macrophages specialized for debris removal. Unlike cells
undergoing necrosis as a result of accidental injury, apoptotic
cells do not rupture and release none of their contents. This
difference is highly significant because release of cellular
components causes a rapid series of local reactions and
immigration of leukocytes in an elaborate reaction called an
inflammatory response. Such a response is unwanted when cells
are routinely eliminated following DNA damage or as part of a
normal development process. These routine cell eliminations
therefore occur rapidly and without repercussions by apoptosis.

42. With their condensed nuclear
chromatin, such cells may
superficially resemble some mitotic
cells. Shown here are apoptotic cells
(A) in epithelium of a villus from the
lining of the small intestine

43. In a corpus luteum beginning
to undergo involution

44. Epithelium of a uterine
endometrial gland at the
onset of menstruation

45. Late apoptosis—formation of apoptotic
bodies
TEM of a cell in late apoptosis shows that during this process the cell's shape changes
radically and large cytoplasmic vesicles (blebs) are formed. These detach from the cell
and often separate one from another, but remain contained within plasma membrane
so that no cytoplasmic contents are released into the extracellular space. The
membrane surrounding such apoptotic bodies is changed in such a way that the blebs
are recognized by neighboring cells or macrophages and are very rapidly
phagocytosed. The rapid formation and engulfment of such blebs without their
disruption allow apoptosis to occur without eliciting an inflammatory reaction.

46. Thank you for attention!