Babies born with this disease don't develop ganglion cells specialized nerve cells in the large intestine, which trigger contractions to push feces through the colon and out the rectum. The result is chronic constipation and intestinal obstructions requiring surgery, sometimes immediately after birth.
Scientists have known for years that Hirschsprung's is a genetic disease, and some of the mutations associated with the disorder have been identified. But no one knew exactly how these mutations impaired the development of the intestinal nervous system.
Based on new research data, U-M scientists now say the basic problem is that neural crest stem cells, which give rise to nerves in the embryonic digestive system, never reach the lower part of the developing gut.
Details of the U-M study will be published in the Aug. 15 issue of Science. It is the first published paper linking Hirschsprung's disease to functional defects in neural crest stem cells, or NCSCs.
"Other scientists found that mutations associated with Hirschsprung's disease cause changes in the proliferation, survival and migration of neural crest cells," says Sean J. Morrison, Ph.D., a Howard Hughes Medical Institute assistant investigator and assistant professor of internal medicine and of cell and development biology in the U-M Medical School. "But it was unclear exactly which neural crest cells were affected or how these changes impaired the formation of the intestinal nervous system."
"We found that the mutated genes causing Hirschsprung's disease act in neural crest stem cells to impair their ability to form a normal intestinal nervous system," Morrison adds.