Nerves in the gut


Hirschprung disease is the result of incomplete development of the enteric nervous system (ENS) within the bowel. The ENS is originates from enteric neural crest–derived cells, which proliferate and migrate to colonize the intestine during embryonic development. While there is some genetic component underlying Hirshprung disease, the variability of disease manifestation suggests that additional factors influence disease progression. Jonathan Lake and colleagues at Washington University used zebrafish to screen for compounds that resulted in improper ENS development and identified the commonly used immunosuppressant mycophenolic acid (MPA) as an inhibitor of ENS formation. In mouse models of Hirschprung disease, treatment of pregnant females with MPA exacerbated disease symptoms and greatly reduced ENS development in the bowel. Furthermore, treatment of isolated enteric neural crest–derived cells with MPA inhibited proliferation, survival, and lamellipodia formation, a process required for migration. These data indicate that exposure to factors that reduce cell proliferation in utero exacerbate Hirschprung disease symptoms in offspring genetically predisposed to the disease. The above image depicts two fetal mouse colons and their developing enteric nervous systems (ENS) just prior to the completion of colonization by ENS precursors. Lineage-marked neural crest derivatives are shown in green, neuronal fibers are stained blue, and the transcription factor SOX10 is shown in red.

Published October 15, 2013, by Corinne Williams

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Hirschsprung-like disease is exacerbated by reduced de novo GMP synthesis
Jonathan I. Lake, … , Brittany L. Graham, Robert O. Heuckeroth
Jonathan I. Lake, … , Brittany L. Graham, Robert O. Heuckeroth
Published November 1, 2013; First published October 15, 2013
Citation Information: J Clin Invest. 2013;123(11):4875-4887. https://doi.org/10.1172/JCI69781.
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Research Article Gastroenterology

Hirschsprung-like disease is exacerbated by reduced de novo GMP synthesis

Abstract

Hirschsprung disease (HSCR) is a partially penetrant oligogenic birth defect that occurs when enteric nervous system (ENS) precursors fail to colonize the distal bowel during early pregnancy. Genetic defects underlie HSCR, but much of the variability in the occurrence and severity of the birth defect remain unexplained. We hypothesized that nongenetic factors might contribute to disease development. Here we found that mycophenolate, an inhibitor of de novo guanine nucleotide biosynthesis, and 8 other drugs identified in a zebrafish screen impaired ENS development. In mice, mycophenolate treatment selectively impaired ENS precursor proliferation, delayed precursor migration, and induced bowel aganglionosis. In 2 different mouse models of HSCR, addition of mycophenolate increased the penetrance and severity of Hirschsprung-like pathology. Mycophenolate treatment also reduced ENS precursor migration as well as lamellipodia formation, proliferation, and survival in cultured enteric neural crest–derived cells. Using X-inactivation mosaicism for the purine salvage gene Hprt, we found that reduced ENS precursor proliferation most likely causes mycophenolate-induced migration defects and aganglionosis. To the best of our knowledge, mycophenolate is the first medicine identified that causes major ENS malformations and Hirschsprung-like pathology in a mammalian model. These studies demonstrate a critical role for de novo guanine nucleotide biosynthesis in ENS development and suggest that some cases of HSCR may be preventable.

Authors

Jonathan I. Lake, Olga A. Tusheva, Brittany L. Graham, Robert O. Heuckeroth

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