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eration of the progenitor, might also direct the progen-
itor cells to either a neuronal or glial lineage. In cell cul-
tures, one can add defined factors and assay the effects
on the production of either neurons or glia from the
progenitor cells. These kinds of studies have led to
some general principles, but also to many conflicting
results that appear to depend on the region of the
nervous system and the age of the embryo from which
the cultures were derived. For example, FGF2 and
Neurotrophin3 promote progenitor cells isolated from
brain to develop primarily as neurons in most studies
(Qian et al., 1998; Ghosh and Greenberg, 1995), and
adding EGF (Kilpatrick and Bartlett, 1995), or CNTF
(ciliary neuronotrophic factor; Bonni et al., 1997) to
CNS cultures causes the cells to develop as astrocytes.
However, members of the TGF-beta superfamily of
molecules, like BMP2 and BMP4 , have also been shown
to have effects on the multipotent progenitor cells,
causing them to develop as neurons under some
culture conditions (Loturco, 1997) and as astrocytes
under others (Gross et al., 1997). Along these same
lines, PDGF (platelet-derived growth factor) promotes
oligodendroglial development in some assays (Raff et
al., 1988) and neurons in other assays (Williams et al.,
1997). The various factors that control the relative ratios
of neurons and glia in the nervous system must even-
tually get translated to the nucleus and activate either
the neuronal or glial program of gene expression, and
recent evidence indicates that CNTF and BMP2 act syn-
ergistically to activate the promoter of a critical astro-
cyte gene, GFAP; STAT binds directly to the GFAP
promoter and activates the gene. Thus, this provides a
direct transcriptional connection between the signaling
molecule and a glial-specific gene. Together, while
these studies highlight the complexity of the process of
neurogenesis, the primary molecular pathways that
promote neurogenesis and gliogenesis can be summa-
rized as shown in Figure 3.11. However, it should also
be noted that most of this work has been done in vitro,
and so it is not known whether all these factors will
have the same effects in vivo, in the intact ventricular
zone. Nevertheless, studies of the effects of EGF and its
receptor activation have shown that, even in vivo, this
factor acts primarily to promote the production of
astrocytes (Kuhn et al., 1997; Burrows et al., 1997), and
biases cells away from neuronal differentiation.
One part of the central nervous system that has been
particularly well characterized for its potential to form
glia is the optic nerve. Raff and his colleagues have
taken advantage of the fact that neurons do not
develop in the optic nerve to carefully study the glial
lineages in restricted glial progenitors (Figure 3.12).
The nerve contains both astrocytes and oligodendro-
cytes, and in vitro studies have shown that a particular
A
B
C
EGL
Shh
Purkinje
cells
D
Cerebral
cortex
Mid br ain
Cerebellum
Striatum
FIGURE 3.10 Sonic hedgehog secreted by neurons stimulates pro-
genitor proliferation. The Shh mitogenic pathway is important in
many regions of the brain, particularly those of the dorsal brain, like
the cerebellum, the cerebral cortex, and the midbrain. Shh is pro-
duced by the differentiated neurons (red) to feed back on the pro-
genitors to maintain their proliferation and ensure that the correct
number of neurons is generated during development. In the
cerebellum, for example, the Shh released from the Purkinje cells
stimulates the granule cell progenitors to make more granule cells.
(Modified from Ruiz i Altaba, 2002)
THE GENERATION OF NEURONS
AND GLIA
The nervous system contains both neurons and glia,
and both basic types of cells are produced in highly
stereotypic ratios. What factors control the relative
ratios of neurons and glia in the brain? Early in the
development of the CNS, many, if not all, of the pro-
genitor cells have the capacity to generate both neurons
and glia. Retroviral lineage studies have shown that,
for many regions of the nervous system, neurons,
astrocytes, and oligodendrocytes can arise from a
single infected progenitor cell. Davis and Temple (1994)
have isolated progenitor cells from the embryonic cere-
bral cortex and cultured them as individual cells; they
found that neurons, astrocytes, and oligodendrocytes
can arise from a single progenitor cell in vitro. At later
stages of development, the lineages of these cell classes
can become separate. When cerebral cortical progeni-
tor cells are labeled relatively late in development, the
progeny of an infected cell may be restricted to only
astrocytes or only neurons (Parnevales et al., 1991;
Luskin et al., 1993). However, regardless of whether
neurons and glia are made from a single division of a
progenitor, as in some regions of the nervous system,
or through separate lineages, the question of how these
two very different cell types arise is an important one
(Jacobson, 1977).
Cell culture studies have suggested that extracellu-
lar signaling factors, like those that control cell prolif-
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