Development profile of neuron-specific enolase in human gut and its implications in Hirschsprung's disease

The most widely held view on the pathogenesis of Hirschsprung's disease as an arrest of neuroblast migration in the gut was based on the hypothesis of a single craniocaudal gradient of development of enteric neurons. Recent experimental studies in animals, however, have revived a contradictory hypothesis of a dual gradient of neuronal development; such data are not available in humans. To test these hypotheses in humans, we studied the pylorus, ileum, and colon of 28 fetuses with gestational ages of 9-21 wk, using immunohistochemical localization of neuron-specific enolase, a specific neuronal marker indicative of differentiation. Development of the enteric nervous system was shown to be most advanced in the pylorus, less so in the colon, and least so in the ileum. The findings support the hypothesis of a dual gradient of neuronal development proceeding from both ends to the middle of the gut in midtrimester human fetuses and suggest that the pathogenesis of Hirschsprung's disease needs to be reconsidered.