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expressed by the neural crest cells, like p75
NTR
, Sox10 or Cadherin-6, are not
downregulated. Thus Sox10 controls the expression of ErbB3 in neural crest
cells. In accordance, all phenotypes present in ErbB3 mutants are also present
in Sox10 mutant mice; e.g., the sympathetic nervous system is severely
hypoplastic.
Other Sox10 target genes also exist, i.e., Sox10 controls not only ErbB3
expression, and phenotypes exist in Sox10 mutant mice that are not present
in the ErbB3 mutants. We discovered one such phenotype: an impaired
differentiation of neural crest cells into early Schwann cell precursors in
the Sox10 mutant mice. Many genes expressed by neural crest cells are
turned off in neurons, but remained expressed in the developing glial cells.
Markers that distinguish neural crest cells from newly formed glia in the
peripheral nervous system are scarce. However, brain-specific fatty acid
binding protein (B-FABP) is not detectable in neural crest cells, but is easily
detected in peripheral glial populations. For example, no B-FABP-positive
cells along spinal nerves or in dorsal root ganglia are found at E10.5 in mice
on lumbar axial levels by immunohistochemistry, but they are abundant at
E11.5. Non-overlapping cell populations stain with B-FABP- and neuron-
specific antibodies. Several days later, the S100-antigen appears in satellite
cells of dorsal root ganglia or in Schwann cells and is co-expressed with
B-FABP. B-FABP therefore distinguishes glia from neural crest cells and
neurons during early stages of development of the peripheral nervous
system. In homozygous Sox10 mutant mice, B-FABP-positive cells are
missing along spinal nerves and in the dorsal root ganglia at E11.5,
indicating that glial differentiation is affected. This does not reflect simply a
delay of differentiation, since B-FABP-positive cells are also absent at E12.5
in the Sox10 mutant mice. However, remaining undifferentiated neural crest
cells can be detected at these sites, indicating that the mutation does not
simply affect the survival of gliogenic neural crest progenitors. In ErbB3
mutant embryos, B-FABP-positive cells are abundant in the ganglia but are
rare along the nerves. Thus, glial cells that express B-FABP can be formed,
but their numbers lining the nerves are reduced in accordance with the
severe reduction in the numbers of neural crest cells that line developing
axon tracts at earlier developmental stages in ErbB3 mutant mice (Britsch et
al., 2001).
c-Ret and Eph tyrosine kinase receptors and the development
of neural crest cells
In addition to the above described function of Nrg1 and the ErbB2/ErbB3
receptors in development of the neural crest analysed in my laboratory,
