Vitamin A facilitates enteric nervous system precursor migration by reducing Pten accumulation

Development. 2010 Feb;137(4):631-40. doi: 10.1242/dev.040550.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Disease Models, Animal
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Enteric Nervous System / cytology
  • Enteric Nervous System / embryology*
  • Enteric Nervous System / metabolism*
  • Female
  • Glial Cell Line-Derived Neurotrophic Factor / pharmacology
  • Heterozygote
  • Hirschsprung Disease / etiology
  • Hirschsprung Disease / genetics
  • Hirschsprung Disease / metabolism
  • Hirschsprung Disease / prevention & control
  • Humans
  • In Vitro Techniques
  • Maternal Nutritional Physiological Phenomena
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Pregnancy
  • Receptors, Retinoic Acid / antagonists & inhibitors
  • Receptors, Retinoic Acid / metabolism
  • Retinol-Binding Proteins, Plasma / deficiency
  • Retinol-Binding Proteins, Plasma / genetics
  • Signal Transduction
  • Tretinoin / pharmacology
  • Vitamin A / metabolism*
  • Vitamin A Deficiency / complications
  • Vitamin A Deficiency / embryology
  • Vitamin A Deficiency / genetics
  • Vitamin A Deficiency / metabolism


  • Glial Cell Line-Derived Neurotrophic Factor
  • Rbp4 protein, mouse
  • Receptors, Retinoic Acid
  • Retinol-Binding Proteins, Plasma
  • Vitamin A
  • Tretinoin
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Pten protein, mouse