Enteric neuron imbalance and proximal dysmotility in ganglionated intestine of the Sox10(Dom/+) Hirschsprung mouse model.

BACKGROUND & AIMS: In Hirschsprung disease (HSCR), neural crest-derived progenitors (NCPs) fail to completely colonize the intestine so that the enteric nervous system (ENS) is absent from distal bowel. Despite removal of the aganglionic region, many HSCR patients suffer from residual intestinal dysmotility. To test the hypothesis that inappropriate lineage segregation of NCPs in proximal ganglionated regions of the bowel could contribute to such postoperative disease, we investigated neural crest (NC)-derived lineages and motility in ganglionated, postnatal intestine of the Sox10(Dom/+) HSCR mouse model. METHODS: Cre-mediated fate-mapping was applied to evaluate relative proportions of NC-derived cell types. Motility assays were performed to assess gastric emptying and small intestine motility while colonic inflammation was assessed by histopathology for Sox10(Dom/+) mutants relative to wildtype controls. RESULTS: Sox10(Dom/+) mice showed regional alterations in neuron and glia proportions as well as Calretinin+ and nNOS+ neuronal subtypes. In the colon, imbalance of enteric NC derivatives correlated with the extent of aganglionosis. All Sox10(Dom/+) mice exhibited reduced small intestinal transit at 4-weeks of age, and at 6-weeks, Sox10(Dom/+) males had increased gastric emptying rates. Sox10(Dom/+) mice surviving to 6-weeks of age had little or no colonic inflammation when compared to wildtype littermates, suggesting that these changes in GI motility are neurally mediated. CONCLUSIONS: The Sox10(Dom) mutation disrupts the balance of NC-derived lineages and affects GI motility in the proximal, ganglionated intestine of adult animals. This is the first report identifying alterations in enteric neuronal classes in Sox10(Dom/+) mutants, which suggests a previously unrecognized role for Sox10 in neuronal subtype specification.