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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 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

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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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Figure 1

MPA inhibited ENS development in developing zebrafish and mouse.

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MPA inhibited ENS development in developing zebrafish and mouse.
(A–C) D...
(A–C) Developing WT zebrafish were exposed to DMSO or MPA from 34 to 96 hpf. (A) Larvae (N > 200) were immunostained for neuronal marker HuC/HuD. (B) Images in A merged with transmitted light. Filled arrowheads denote most caudal enteric neuron; open arrowheads denote vents. (C) Average uncolonized distal intestine, plotted vs. MPA dose and compared with control. (D–F) MPA exposure by maternal intraperitoneal injection from E10.5 to E12.5 impaired enteric neuron colonization of the mouse hindgut at E13.5 (D), as visualized by the neuronal marker TuJ1 (left side, ileocecal junction; dotted line, colon outline). The position within each E13.5 colon of the most caudal (E) neuronal process (marked by TuJ1) or (F) ENCDC cell body (ascertained by the lineage marker EYFP or by SOX10 staining in EYFP– littermates) in each E13.5 fetus is plotted for each MPA dose and mouse strain (thick lines denote mean). Scale bars: 250 μm (A and B); 1 mm (D). ***P < 0.001, Kolmogorov-Smirnov test (C); ANOVA and t test (E and F).

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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