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Hirschsprung disease (HSCR) is characterized by absence of enteric neurons from the distal colon and severe intestinal dysmotility. To understand the pathophysiology and genetics of HSCR we developed a unique zebrafish model that allows combined genetic, developmental and  in vivo  physiological studies. We show that  ret  mutant zebrafish exhibit cellular, physiological and genetic features of HSCR, including absence of intestinal neurons, reduced peristalsis, and varying phenotype expressivity in the heterozygous state. We perform live imaging experiments using a UAS-GAL4 binary genetic system to drive fluorescent protein expression in ENS progenitors. We demonstrate that ENS progenitors migrate at reduced speed in  ret  heterozygous embryos, without changes in proliferation or survival, establishing this as a principal pathogenic mechanism for distal aganglionosis. We show, using live imaging of actual intestinal movements, that intestinal motility is severely compromised in  ret  mutants, and partially impaired in  ret  heterozygous larvae, and establish a clear correlation between neuron position and organised intestinal motility. We exploited the partially penetrant  ret  heterozygous phenotype as a sensitised background to test the influence of a candidate modifier gene. We generated  mapk10  loss-of-function mutants, which show reduced numbers of enteric neurons. Significantly, we show that introduction of  mapk10  mutations into  ret  heterozygotes enhanced the ENS deficit, supporting  MAPK10  as a HSCR susceptibility locus. Our studies demonstrate that  ret  heterozygous zebrafish is a sensitized model, with many significant advantages over existing murine models, to explore the pathophysiology and complex genetics of HSCR.

plos genetics

A Novel Zebrafish ret Heterozygous Model of Hirschsprung Disease Identifies a Functional Role for mapk10 as a Modifier of Enteric Nervous System Phenotype Severity