Contemporary Approaches Toward Understanding the Pathogenesis of Hirschsprung Disease

Hirschsprung disease (HD), or congenital aganglionosis coli, is a birth defect with heterogeneous causes. In an effort to understand the molecular and cellular bases for this disorder, researchers have investigated enteric neurodevelopment in normal animals and compared these findings with observations of inbred animal strains that develop aganglionosis coli due to mutations at specific genetic loci. Recent technological advances, including use of retroviral and fluorescent lineage makers, immunohistochemical probes, and transgenic mice, have provided insights into the origins, behavior, and properties of enteric neuroblasts. Experiments with mutant murine embryos indicate that aganglionosis coli results from primary failure of neural crest-derived neuroblasts to colonize the distal colon. In at least one model, impaired colonization by neuroblasts may be secondary to environmental defects restricted to colonic mesenchyme. The discovery that human piebald trait, a hereditary disorder with a high incidence of HD, is caused by mutations in a growth factor receptor highlights the importance of regulatory intercellular interactions between nonneuroblastic mesenchyme and neuroblasts during normal development of the enteric nervous system. These observations, coupled with advances in molecular genetics, set the stage for dramatic progress in this field of research in the near future.