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Stem-cell defect underlies common genetic disorder

Howard Hughes Medical Institute researchers have found that Hirschsprung disease, one of the most common genetic disorders, is caused by a defect that blocks neural stem cells from forming nerves that control the lower intestine.

Hirschsprung disease occurs in one in 5,000 live births and causes a potentially fatal disorder that prevents the proper transport of food through the gut. The new findings suggest that it might one day be possible to correct the disease by transplanting neural stem cells from a different part of the gut.

Neural crest stem cells (NCSCs) are cells that mature into neurons and supporting neural cells found in the gut. The studies provide important general insight into how stem cells -- the immature cells that can develop into mature nerve and other cells -- are controlled. While the properties of stem cells have been widely studied, relatively little is known about how they are regulated during development.

The researchers, led by Howard Hughes Medical Institute (HHMI) investigator Sean J. Morrison, HHMI associate Toshihide Iwashita, and graduate student Eve Kruger at the University of Michigan, published their findings in the August 15, 2003, issue of Science.

"Some of the genetic mutations that cause Hirschsprung have been identified, but they explain only about half the cases," said Morrison. "Our work identifies new genes whose mutations might underlie the disease. We've found the mechanism by which one type of mutation impairs the function of the neural crest stem cells that give rise to the enteric nervous system."

The researchers began by conducting a global comparison of genes expressed in whole mouse fetuses with those genes expressed only in the fetal gut NCSCs. To make this comparison, they applied RNA extracts from the two sources to microarrays, or "gene chips," which are arrays of thousands of gene probes that can signal the acti
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
14-Aug-2003


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