Neural crest requires Impdh 2 for development of the enteric nervous system, great vessels, and craniofacial skeleton
| Autor: | Jonathan I. Lake, Albert G. Zimmermann, Marina Avetisyan, Robert O. Heuckeroth |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Gene isoform medicine.medical_specialty RNA Untranslated animal structures Transgene Wnt1 Protein Biology Enteric Nervous System Article 03 medical and health sciences chemistry.chemical_compound Fetus IMP Dehydrogenase Genes Reporter Internal medicine medicine In Situ Nick-End Labeling Animals Hirschsprung Disease Inosine Molecular Biology Alleles Mice Knockout Recombination Genetic Integrases Myocardium Skull Neural crest Embryo Cell Biology Cell biology Mice Inbred C57BL 030104 developmental biology Endocrinology chemistry Bromodeoxyuridine Neural Crest Organ Specificity Face embryonic structures Enteric nervous system Female Gene Deletion medicine.drug Developmental Biology |
| DOI: | 10.17615/c8gh-gb59 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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