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Fluorescent dye
Multipotent Neural Crest Progenitor
Inductive
factor
Wnt
(late)
BMP2/4
(TGF
Wnt
(early)
TGF b 1-3
(BMP2/4)
GGF
24 hours
b
1-3)
Neural crest
progenitor
Sensory
neuron
Smooth
Muscle
FIGURE 4.14 Different neural crest fates are promoted by a dis-
tinct set of extracellular signaling molecules. (After Dorsky et al.,
2000)
Cell type
Sensory
Neurons
Autonomic
Neurons
Schwann
cells
Pigment
cells
Sympathetic
neuron
Schwann cell
Aorta
mine them toward a sensory fate. It appears that the
sensory cells of the dorsal root ganglia (DRG) inhibit
other crest cells from assuming this fate. If the cells that
normally make the DRGs are ablated, then later migrat-
ing crest cells will differentiate into sensory neurons
(Zirlinger et al., 2002).
Experiments with purified populations of neural
crest cells in culture suggest that different factors are
involved in these restrictions (Figure 4.14) (Groves and
Anderson, 1996; Anderson et al., 1997; Dorsky et al.,
2000). It turns out that where cells encounter such
factors on their migration route is very important in
shaping appropriate destinies. BMPs are expressed in
the dorsal aorta, where sympathetic ganglia form.
BMPs turns on a program of neurogenesis in sympatho-
adrenal (SA) cells (i.e. cells that are either part of the
sympathetic nervous system or cells that are part of
the adrenal gland) by inducing the expression of the
paired domain transcription factor Phox2b which is
required for the development of all of the autonomic
nervous system and the proneural bHLH gene MASH1 ,
which is required for the expression of neuronal
markers in autonomic neurons (Pattyn et al., 1999;
Schneider et al., 1999). However, further cues are
needed if these cells are to become mature neurons. SA
progenitors plated on a laminin-containing substrate
in the absence of any growth factor form short, neuron-
like processes. These processes become more extensive
when the growth factor FGF is added to the medium,
whereas the neurotrophic factor NGF, which is needed
for the survival of sympathetic neurons (see Chapter
7) has no effect at this stage. The SA progenitors are
Parasympathetic
neuron
FIGURE 4.13 Fates and migration of neural crest cells. A single
progenitor cell is injected with a lineage tracer, and its progeny are
followed as they migrate out of the neural tube. Some may become
sensory neurons, while others become Schwann cells or neurons of
the autonomic nervous system. Environments these cells pass
through on their migration routes influence their fate choice. (After
Bronner-Fraser and Fraser, 1991)
factors, and the migrating cells respond to these factors
and each other in a way that limits their potential. Ini-
tially, neural crest cells are multipotent, and labeling of
single progenitors at the earliest stages of migration
shows that these cells can give rise to a wide variety of
derivatives (Bronner-Fraser and Fraser, 1988) (Figure
4.13). But as the cells migrate along particular routes,
they segregate into several classes of more specialized
progenitors. Thus, as development proceeds, they
become more restricted. In the trunk region, an early
decision separates postmigratory crest cells that will
become the sensory progenitors, which remain in the
somitic mesodermal region and express the proneural
bHLH transcription factor Neurogenin (Nrgn2), from
the autonomic progenitors, which do not (Lo et al.,
2002). Transplantation studies with these two types of
progenitors shows they can no longer make the full
array of cell types. Nrgn2 is already expressed in pre-
migratory crest cells and appears to bias but not deter-
 
 
 
 
 
 
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