Healthcare and Medicine Reference
In-Depth Information
are beginning to be understood. Many of the same
molecular mechanisms that control the proliferation of
progenitors in the nervous system are also important
for the control of cell division in other tissues. Through
the analysis of mutations in yeast cells that disrupt
normal cell cycle, a number of the components of the
molecular machinery controlling cell cycle have been
identified. Remarkable progress has been made in
recent years in understanding the proteins that control
the mitotic cell cycle. An intricate sequence of protein
interactions controls and coordinates the progress of a
cell through the stages of cell replication. There has
been a considerable amount of conservation of this
molecular mechanism over the millions of years of
evolution from the simplest eukaryotic cells, like yeast,
to more complex animals and plants (see BOX).
Cyclins are a group of proteins that show dramatic
changes in their expression levels that correlate with
specific stages of the cell cycle. The association of
cyclins with another class of proteins, called the cyclin-
dependent kinases ( Cdk ), causes the activation of these
kinases and the subsequent phosphorylation of sub-
strate proteins necessary for progression to the next
phase of the cell cycle. Different cyclin/cdk pairs are
required at different stages of the cell cycle. For
example, the binding of cyclinB to Cdc2 forms an active
complex that causes a cell to progress through the M-
phase of the cycle, while the association of cyclinD and
cdk4 or cdk6 causes these kinases to phosphorylate pro-
teins necessary for progression from G1- to S-phase.
One of the more dramatic examples of the importance
of cyclins to the development of the nervous system is
shown in Figure 3.8 (Geng et al., 2001). In this example,
the cyclinD1 gene was eliminated in mice using
homologous recombination; the retinas of these mice
are much smaller than those of normal mice because
the progenitor cells of the cyclinD1 - / - mice fail to pro-
liferate at the normal rate.
One way in which the cyclinD1/Cdk4 complex
causes cells to enter S-phase is by phosphorylating a
protein called retinoblastoma or Rb (see Cell Cycle
Box). This phosphorylation causes the Rb protein to
release another transcription factor, E2F , and allows
the E2F protein to activate many genes that push the
cell into S-phase. The Rb protein received its name
from a childhood tumor of the retina, retinoblastoma,
since defects in this gene cause uncontrolled retinal
progenitor proliferation. In fact, the Rb gene was the
first of a class of genes called tumor suppressors to be
identified. Children who inherit a mutant copy of the
Rb gene develop retinoblastoma when the second
allele of this gene is mutated in a progenitor cell in the
retina. E2F is then free to activate the genes that cause
the progenitor to progress through the cell cycle, and
there is no active Rb around to stop the process. It is
clear from this example that regulation of progenitor
proliferation is critical both for making a normal retina
and for preventing the uncontrolled cell proliferation
that leads to cancer.
Other critical negative regulators of the cyclin-
dependent kinases, p27 and p21 , are also expressed in
the nervous system, and they are expressed in the final
mitotic cycle of a progenitor, causing it to exit the cell
cycle and differentiate into neurons or glia. The p27
gene, for example, codes for a protein that interacts
with the Cdk proteins but instead of activating the Cdk
proteins, the p27 protein inhibits the function of the
Cdk it binds, and is therefore called a Cdk-I (for Cdk
inhibitor). Deletion of the p27 gene in mice causes the
opposite phenotype as that of the cyclinD1 knockout;
that is, there is an overproduction of cells in the brain
and other regions of the body in animals deficient in the
p27 gene. Figure 3.8 shows an example of continued
proliferation in the retina of a mouse with the p27 gene
eliminated. Although the retina is not twice the size of
a normal mouse, overall the mice are larger, and there
are additional cells in the outer nuclear layer of the p27 -
deficient mice (Figure 3.8, arrows). What if both p27
and cyclinD1 are knocked out in mice? The surprising
result is that the retina is now relatively normal (Figure
3.8 D). This implies that while these are key regulators
of the cell cycle in normal development, when both
the positive regulator and the negative regulator are
removed, the system reaches a new balance. Overall,
studies of cell-cycle genes in the CNS have led to the
conclusions that these are critical regulators of neuro-
genesis and gliogenesis, but much more needs to be
learned about their specific functions and interactions.
CELL INTERACTIONS CONTROL
THE NUMBER OF CELLS MADE
BY PROGENITORS
In many tissues in the body, secreted signaling
factors have been identified that stimulate or inhibit
the progress of mitotically active cells through the cell
cycle. The signals that stimulate the proliferation of the
mitotic cells are called growth factors or mitogens and
were named for the tissue or cell type where they were
first found to have mitogenic effects. For example,
fibroblast growth factor (FGF) was first found to
promote the proliferation of fibroblasts in cell cultures,
whereas epidermal growth factor (EGF) was discov-
ered as a mitogen for epidermal cells in vitro. These
growth factors most commonly act to control the pro-
gression from G1- to S-phase of the cell cycle, and
Search Pocayo ::




Custom Search