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Science 301 (5635): 972-976

Copyright © 2003 by the American Association for the Advancement of Science

Hirschsprung Disease Is Linked to Defects in Neural Crest Stem Cell Function

Toshihide Iwashita,* Genevieve M. Kruger,* Ricardo Pardal, Mark J. Kiel, Sean J. Morrison{dagger}

Abstract: Genes associated with Hirschsprung disease, a failure to form enteric ganglia in the hindgut, were highly up-regulated in gut neural crest stem cells relative to whole-fetus RNA. One of these genes, the glial cell line–derived neurotrophic factor (GDNF) receptor Ret, was necessary for neural crest stem cell migration in the gut. GDNF promoted the migration of neural crest stem cells in culture but did not affect their survival or proliferation. Gene expression profiling, combined with reverse genetics and analyses of stem cell function, suggests that Hirschsprung disease is caused by defects in neural crest stem cell function.

Howard Hughes Medical Institute and Departments of Internal Medicine and Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109–0934, USA.

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* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: seanjm{at}

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