Defective Endothelin Receptor B Signaling and Hirschsprung's Disease

Abstract

Both sacral- and cranial-derived neural crest cells populate the gut tube, and there remains debate about where and what each contributes. This issue is especially important in understanding the variations seen in infants with Hirschsprung's disease. Our previous work followed labeled cranial crest cells along the wall of the gut tube, and documented the relation among leading edge and follower crest populations. By mating Wnt-1 cre and floxed YFP and endothelin receptor B (EDNRB) mice, we generated pups whose enteric neural crest derived cells express YFP but lack a functional EDNRB. These pups lack neurons in the distal colon, but do show a robust array of fibers, some of which originate in the pelvic ganglion. Individual or aggregates of neurons associated with these fibers reside either in the interface between the circular and longitudinal muscle or in the adventia. Neurons in the proximal portion of the null colon show a change in transmitter expression. The percentage of neurons with nitric oxide synthase increased 2–3 fold in the null colon but not the null ileum, while no increase occurred in the same tissues from hetrozygous mice. We conclude that the sacral-crest derived cells contribute few neurons to the colon of null EDNRB mice. Funded by NIH DK081634