Vitamin A facilitates enteric nervous system precursor migration by reducing Pten accumulation.
Hirschsprung disease is a serious disorder of enteric nervous system (ENS) development caused by the failure of ENS precursor migration into the distal bowel. We now demonstrate that retinoic acid (RA) is crucial for GDNF-induced ENS precursor migration, cell polarization and lamellipodia formation, and that vitamin A depletion causes distal bowel aganglionosis in serum retinol-binding-protein-deficient (Rbp4(-/-)) mice. Ret heterozygosity increases the incidence and severity of distal bowel aganglionosis induced by vitamin A deficiency in Rbp4(-/-) animals. Furthermore, RA reduces phosphatase and tensin homolog (Pten) accumulation in migrating cells, whereas Pten overexpression slows ENS precursor migration. Collectively, these data support the hypothesis that vitamin A deficiency is a non-genetic risk factor that increases Hirschsprung disease penetrance and expressivity, suggesting that some cases of Hirschsprung disease might be preventable by optimizing maternal nutrition.
Fu
Ming
M
Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, USA.
Sato
Yoshiharu
Y
Lyons-Warren
Ariel
A
Zhang
Bin
B
Kane
Maureen A
MA
Napoli
Joseph L
JL
Heuckeroth
Robert O
RO
D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D017615:Enteric Nervous System / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology; D006579:Heterozygote; D006627:Hirschsprung Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D066298:In Vitro Techniques; D039382:Maternal Nutritional Physiological Phenomena; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D014212:Tretinoin / Q000494:pharmacology; D014801:Vitamin A / Q000378:metabolism*; D014802:Vitamin A Deficiency / Q000150:complications / Q000196:embryology / Q000235:genetics / Q000378:metabolism
D051100:Glial Cell Line-Derived Neurotrophic Factor; C502487:Rbp4 protein, mouse; D018168:Receptors, Retinoic Acid; D054839:Retinol-Binding Proteins, Plasma; D014801:Vitamin A; D014212:Tretinoin; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse