SOX10 MUTATION DISRUPTS NEURAL CREST DEVELOPMENT IN DOM HIRSCHSPRUNG MOUSE MODEL

Hirschsprung disease (HSCR, MIM #142623) is a multigenic neurocristopa thy (neural crest disorder) characterized by absence of enteric gangli a in a variable portion of the distal colon. Subsets of HSCR individua ls also present with neural crest-derived melanocyte deficiencies (Hir schsprung-Waardenburg, HSCR-WS, MIM #277580). Murine models have been instrumental in the identification and analysis of HSCR disease genes. These include mice with deficiencies of endothelin B receptor (Ednrb( s-l); refs 1,2) endothelin 3 (Edn3(ls); refs 1,3) the tyrosine kinase receptor cRet(4) and glial-derived neurotrophic factor(5-7). Another m ouse model of HSCR disease, Dom, arose spontaneously at the Jackson La boratory(8). While Dom/+ heterozygous mice display regional deficienci es of neural crest-derived enteric ganglia in the distal colon, Dom/Do m homozygous animals are embryonic lethal(8). We have determined that premature termination of Sox10, a member of the SRY-like HMG box famil y of transcription factors, is responsible for absence of the neural c rest derivatives in Dom mice. We demonstrate expression of Sox10 in no rmal neural crest cells, disrupted expression of both Sox10 and the HS CR disease gene Ednrb in Dom mutant embryos, and loss of neural crest derivatives due to apoptosis. Our studies suggest that Sox10 is essent ial for proper peripheral nervous system development. We propose SOX10 as a candidate disease gene for individuals with HSCR whose disease d oes not have an identified genetic origin.