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G1 phase nearly triples in length. The lengthening of
the G1 period likely reflects some regulatory process
that restricts or slows reentry of the progenitor cells
into the S-phase from G1, consistent with the idea that
a limiting supply of growth factor controls this step
(see next section).
The number of cells generated by a precursor cell in
the ventricular zone depends on the stage of develop-
ment and the region of the nervous system where the
progenitor is located. Progenitor cells from the early
embryonic CNS must generate a considerably greater
number of progeny than those from animals nearing
the end of neurogenesis. Similarly, progenitor cells
from very large regions of the brain must have given
rise to many more cells than those from the spinal cord.
The thymidine studies described above showed that
there were differences in the cell-cycle periods of ven-
tricular zone cells of early and late embryos; thymidine
labeling and, more recently, BrdU labeling of the mitoti-
cally active ventricular zone cells have given some
information as to the number of progeny produced by
the entire population of these cells as development
proceeds. In the early embryonic cerebral cortex, for
example, the number of cells more than doubles each
day. Since it takes approximately a half day for a pro-
genitor cell to generate two daughters, more than half
of the progeny must continue to divide; that is, many
of the cell divisions must produce two mitotically
active daughters. During this early “expansion phase”
of the progenitor cells, most of the cell divisions are
symmetric, generating two additional progenitor cells
(Figure 3.4); however, birthdating studies (see below)
also show that some neurons are born during these
early periods as well, and so some of the divisions
must be asymmetric, generating a mitotically active
daughter and a postmitotic neuron. As development
proceeds, the cell-cycle time becomes progressively
longer, and the number of new cells generated per day
declines. Fewer cell divisions are symmetric and result
in two progenitor cells at later stages of development,
compared to the early stages of embryogenesis.
Instead, in the later stages of neurogenesis, a greater
proportion of the progenitor cells differentiate into
neurons and glia (Caviness, 1996). By the end of neu-
rogenesis, nearly all of the cells leave the cell cycle, and
very few remain to generate new neurons.
The results from the thymidine and BrdU labeling
studies have been nicely complemented by retroviral
labeling of individual progenitor cells (Figure 3.5). The
retroviral labeling technique takes advantage of the
fact that retroviruses will only successfully infect and
integrate their genes into cells that are going through
the cell cycle. The genome of these viruses can be
modified to contain genes that code for proteins not
Stem or “founder” cells
Glial progenitor
neural precursor
FIGURE 3.4 Basic lineage relationships among the cell types
of the central nervous system of vertebrates. Through a variety of
cell cultures and in vivo studies, the relationships among the various
cell classes within the nervous system have been established. The
early cells of the neural tube have the potential to generate an
enormous number of progeny, and as a result are sometimes called
founder cells or stem cells, which undergo symmetric cell divisions
to produce additional founder cells as well as progenitor cells. (The
term stem cells is also used to describe the persistent progenitors
found in adult animals.) It is thought that the early founder cells
also generate progenitor cells that are capable of a more limited
number of cell divisions, and this is the reason that clones of
progenitor cells labeled late in embryogenesis have fewer progeny.
Nevertheless, the late progenitor cells are capable of generating both
neurons and all macroglia, the oligodendrocytes, and the astrocytes.
Although in vitro studies of certain regions of the nervous system,
particularly the optic nerve, have shown that the lineages of astro-
cytes and oligodendrocytes share a common progenitor, known as
the O2A glial progenitor, in the spinal cord, motoneurons and oligo-
dendrocytes share a common progenitor. Thus, the lineage relation-
ships shown may vary depending on the region of the CNS.
normally present in the nervous system but can be
detected easily, such as green fluorescent protein (GFP)
or alkaline phosphatase. Once the virus infects a cell,
and the viral genome is integrated into the cell's DNA,
the viral genes are inherited in all the daughter cells of
the originally infected cell. Another important feature
of this technique is that the virus is typically modified
so that it is incapable of making more virus in the
infected cells and spreading the infection to other cells.
This means that only the daughter cells of the originally
infected progenitors will express the viral genes. If a
retrovirus that contains DNA coding for alkaline phos-
phatase is then injected into the developing brain and
infects some of the proliferating progenitor cells, the
progeny of the infected cells will still express the alka-
line phosphatase gene even in adult animals. Labeling
individual progenitor cells with retroviruses at differ-
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