Cumulative evidence suggests that Hirschsprung disease (HSCR) is the consequence 
of multiple gene interactions that modulate the ability of enteric neural crest 
(NC) cells to populate the developing gut. One of the essential genes for this 
process is the NC transcription factor Sox10. Sox10Dom mice on a mixed genetic 
background show variation in penetrance and expressivity of enteric 
aganglionosis that are analogous to the variable aganglionosis seen in human 
HSCR families. The phenotype of Sox10Dom mice in congenic lines indicates this 
variation arises from modifiers in the genetic background. To determine whether 
known HSCR susceptibility loci are acting as modifiers of Sox10, we tested for 
association between genes in the endothelin signaling pathway (EdnrB, Edn3, 
Ece1) and severity of aganglionosis in an extended pedigree of B6C3FeLe.Sox10Dom 
mice. Single locus association analysis in this pedigree identifies interaction 
between EdnrB and Sox10. Additional analysis of F2 intercross progeny confirms a 
highly significant effect of EdnrB alleles on the Sox10Dom/+ phenotype. The 
presence of C57BL/6J alleles at EdnrB is associated with increased penetrance 
and more severe aganglionosis in Sox10Dom mutants. Crosses between EdnrB and 
Sox10 mutants corroborate this gene interaction with double mutant progeny 
exhibiting significantly more severe aganglionosis. The background strain of the 
EdnrB mutant further influences the phenotype of Sox10/EdnrB double mutant 
progeny implying the action of additional modifiers on this phenotype. Our data 
demonstrates that Sox10-EdnrB interactions can influence development of the 
enteric nervous system in mouse models and suggests that this interaction could 
contribute to the epistatic network producing variation between patients with 
aganglionosis.