Cell Nucleus Biogenesis, Structure and Function
been show to be causative for the autoso-
mal dominant form of this disease. About
50 mutations within
have been de-
scribed that lead to disease states such as
EDMD and closely related disorders. In-
terestingly, lamin mutations seem not to
affect all cell types, and while knockout
mice die soon after birth, it is notable that
individuals with lamin mutations live into
adulthood. This may not be surprising as
natural selection allows the accumulation
of mutations that are not lethal. It is in-
teresting to speculate that mutant lamins
weaken the structure of the lamina to yield
fragile nuclei. These might be especially
susceptible to damage in cells such as
muscle and tendon that are put under sig-
niFcant stress during muscle contraction.
Biogenesis of the Nuclear Envelope During
Cell Proliferation
The process of cell division inevitably de-
mands that a series of profound structural
changes will be required to generate two
genetically identical daughter cells during
mitosis. Prior to mitosis, chromosomes are
dispersed throughout the nuclear interior.
Before the new daughter cells can form,
the chromosomes must condense so one
of each of the daughter chromatids (i.e.
the two equivalent products of DNA repli-
cation for each chromosome) can pass to
the daughter cells. The cell cycle proteins,
and critically at this part of the cell cycle
cdc2 and cyclinB, predominantly through
changes in phosphorylation, drive changes
in chromatin structure that lead to chromo-
some condensation. Other changes lead
to a concomitant dissolution of the nu-
clear periphery. The critical events needed
to achieve this involve changes in the
structure of the nuclear lamina. Changes
in phosphorylation of the lamin proteins
cause disruption of the lamin Flament net-
work. Loss of the chromatin stabilizing
properties of the lamin-chromatin inter-
actions allows an increase in chromatin
mobility so that chromosome condensa-
tion is not impeded. Moreover, as the
lamina disrupts, stabilizing contacts be-
tween the lamina and nuclear envelope
are lost. The new dynamic capabilities
of the nuclear envelope then allow the
membrane to merge with the envelope
networks of the endoplasmic reticulum.
During this process the nuclear pores are
disrupted into a small number of discrete
pore subassemblies. This dissolution of
the nuclear membrane and the concomi-
tant condensation of chromosomes marks
the early stages of mitosis. While this is
by far the most common course of events
during a eukaryotic mitosis it should be
noted that some simple model eukary-
otes – such as the yeast
S. cerevisiae
a closed mitosis where the nuclear mem-
brane remains ostensibly intact during
chromosome separation.
During mitosis, once the chromosomes
have migrated to the poles of the cell, a
central constriction in the cell membrane
leads to the formation of the two new
daughter cells. The cell cycle machinery
now drives nuclear reconstruction. In
essence, the new nuclei form through a
program that is the reverse of the events
that preceded the onset of mitosis. As the
chromosomes begin to expand, patches
on new nuclear lamina are thought to
become associated with the chromatin
and these then engage the endoplasmic
reticulum, which is extruded to surround
the chromosomes, eventually to form the
new nuclear envelopes. Lamin B appears
to associate with chromatin early during
the assembly process while lamin A seems
to remain in the cytoplasm until nuclear
membrane assembly is complete – when
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