Dominant megacolon(Dom) is a mutation in an uncharacterized murine gene which is associated with intestinal aganglionosis and the focal absence of melanocytes in heterozygous animals. The phenotype ofDom/+ heterozygotes is similar to thelethal spottedandpiebald lethalmutations, which are due to defects in endothelin-mediated intercellular signals. In this study, theDβH–nlacZtransgenic marker for enteric neural crest cells is used to study the distribution of enteric neurons and their precursors inDom/+ mice and embryos. Vagal neural crest-derived cells in wild-type embryos colonize the gut in a cranial-to-caudal progression. InDom/+ embryos, colonization was retarded from the earliest stages examined (embryonic Day 11.0), including progression through the small intestine. The early onset of this defect contrasts with impaired neural crest colonization associated with thelethal spottedandpiebald lethalmutations which manifest only in the large intestine. Analysis ofDom/+ ←→ +/+ aggregation chimeras indicated that defective colonization is not an autonomous (intrinsic) property ofDom/+ neuroblasts, but likelethal spottedandpiebald lethal,theDominant megacolonmutation directly or indirectly affects microenvironmental signals which influence the migration, proliferation, and/or survival of enteric neural crest cells.