Survival and glial fate acquisition of neural crest cells are regulated byan interplay between the transcription factor Sox10 and extrinsic combinatorial signaling
C. Paratore et al., Survival and glial fate acquisition of neural crest cells are regulated byan interplay between the transcription factor Sox10 and extrinsic combinatorial signaling, DEVELOPMENT, 128(20), 2001, pp. 3949-3961
The transcription factor Sox10 is required for proper development of variou
s neural crest-derived cell types. Several lineages including melanocytes,
autonomic and enteric neurons, and all subtypes of peripheral glia are miss
ing in mice homozygous for Sox10 mutations. Moreover, haploinsufficiency of
Sox10 results in neural crest defects that cause Waardenburg/Hirschsprung
disease in humans. We provide evidence that the cellular basis to these phe
notypes is likely to be a requirement for Sox10 by neural crest stem cells
before lineage segregation. Cell death is increased in undifferentiated, po
stmigratory neural crest cells that lack Sox10, suggesting a role of Sox10
in the survival of neural crest cells. This function is mediated by neuregu
lin, which acts as a survival signal for postmigratory neural crest cells i
n a Sox10-dependent manner. Furthermore, Sox10 is required for glial fate a
cquisition, as the surviving mutant neural crest cells are unable to adopt
a glial fate when challenged with different gliogenic conditions. In Sox10
heterozygous mutant neural crest cells, survival appears to be normal, whil
e fate specifications are drastically affected. Thereby, the fate chosen by
a mutant neural crest cell is context dependent. Our data indicate that co
mbinatorial signaling by Sox10, extracellular factors such as neuregulin 1,
and local cell-cell interactions is involved in fine-tuning lineage decisi
ons by neural crest stem cells. Failures in fate decision processes might t
hus contribute to the etiology of Waardenburg/Hirschsprung disease.