title: Neural crest requires Impdh2 for development of the enteric nervous system, great vessels, and craniofacial skeleton.
abstract: Mutations that impair the proliferation of enteric neural crest-derived cells (ENCDC) cause Hirschsprung disease, a potentially lethal birth defect where the enteric nervous system (ENS) is absent from distal bowel. Inosine 5' monophosphate dehydrogenase (IMPDH) activity is essential for de novo GMP synthesis, and chemical inhibition of IMPDH induces Hirschsprung disease-like pathology in mouse models by reducing ENCDC proliferation. Two IMPDH isoforms are ubiquitously expressed in the embryo, but only IMPDH2 is required for life. To further understand the role of IMPDH2 in ENS and neural crest development, we characterized a conditional Impdh2 mutant mouse. Deletion of Impdh2 in the early neural crest using the Wnt1-Cre transgene produced defects in multiple neural crest derivatives including highly penetrant intestinal aganglionosis, agenesis of the craniofacial skeleton, and cardiac outflow tract and great vessel malformations. Analysis using a Rosa26 reporter mouse suggested that some or all of the remaining ENS in Impdh2 conditional-knockout animals was derived from cells that escaped Wnt1-Cre mediated DNA recombination. These data suggest that IMPDH2 mediated guanine nucleotide synthesis is essential for normal development of the ENS and other neural crest derivatives.
authors.affiliation: Department of Pediatrics and Department of Developmental Regenerative and Stem Cell Biology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8208, St. Louis, MO 63021, USA.
authors.forename: Jonathan I
authors.initials: JI
authors.lastname: Lake
authors.affiliation: Department of Pediatrics and Department of Developmental Regenerative and Stem Cell Biology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8208, St. Louis, MO 63021, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Avetisyan
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, 125 Mason Farm Rd, Chapel Hill, NC 27599, USA.
authors.forename: Albert G
authors.initials: AG
authors.lastname: Zimmermann
authors.affiliation: Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and The Children's Hospital of Philadelphia Research Institute, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA. Electronic address: Heuckerothr@email.chop.edu.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Heuckeroth
mesh_terms: D000483:Alleles; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D017615:Enteric Nervous System / Q000098:blood supply* / Q000196:embryology* / Q000201:enzymology / Q000473:pathology; D005145:Face / Q000196:embryology*; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000196:embryology; D017353:Gene Deletion; D017930:Genes, Reporter; D006627:Hirschsprung Disease / Q000473:pathology; D007168:IMP Dehydrogenase / Q000172:deficiency / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D019426:Integrases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D009432:Neural Crest / Q000196:embryology* / Q000201:enzymology*; D009928:Organ Specificity; D022661:RNA, Untranslated / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D012886:Skull / Q000196:embryology* / Q000378:metabolism; D051155:Wnt1 Protein / Q000378:metabolism
chemical_list: C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D022661:RNA, Untranslated; D051155:Wnt1 Protein; D007168:IMP Dehydrogenase; C488212:IMPDH2, mouse; C045073:Cre recombinase; D019426:Integrases; D001973:Bromodeoxyuridine
keywords: De novo purine synthesis; Enteric nervous system; Neural crest