Retinoic acid regulates murine enteric nervous system precursor proliferation, enhances neuronal precursor differentiation, and reduces neurite growth in vitro

Dev Biol. 2008 Aug 1;320(1):185-98. doi: 10.1016/j.ydbio.2008.05.524. Epub 2008 May 20.


Enteric nervous system (ENS) precursors undergo a complex process of cell migration, proliferation, and differentiation to form an integrated network of neurons and glia within the bowel wall. Although retinoids regulate ENS development, molecular and cellular mechanisms of retinoid effects on the ENS are not well understood. We hypothesized that retinoids might directly affect ENS precursor differentiation and proliferation, and tested that hypothesis using immunoselected fetal ENS precursors in primary culture. We now demonstrate that all retinoid receptors and many retinoid biosynthetic enzymes are present in the fetal bowel at about the time that migrating ENS precursors reach the distal bowel. We further demonstrate that retinoic acid (RA) enhances proliferation of subsets of ENS precursors in a time-dependent fashion and increases neuronal differentiation. Surprisingly, however, enteric neurons that develop in retinoid deficient media have dramatically longer neurites than those exposed to RA. This difference in neurite growth correlates with increased RhoA protein at the neurite tip, decreased Smurf1 (a protein that targets RhoA for degradation), and dramatically decreased Smurf1 mRNA in response to RA. Collectively these data demonstrate diverse effects of RA on ENS precursor development and suggest that altered fetal retinoid availability or metabolism could contribute to intestinal motility disorders.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation / drug effects*
  • Cell Lineage / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Enteric Nervous System / cytology*
  • Enteric Nervous System / drug effects
  • Enteric Nervous System / embryology
  • Gene Expression Regulation, Developmental / drug effects
  • Mice
  • Neurites / drug effects*
  • Neurites / metabolism*
  • Neuroglia / cytology
  • Neuroglia / drug effects
  • Stem Cells / cytology*
  • Stem Cells / drug effects
  • Tretinoin / metabolism
  • Tretinoin / pharmacology*
  • Ubiquitin-Protein Ligases / metabolism
  • rhoA GTP-Binding Protein / metabolism


  • Tretinoin
  • Smurf1 protein, mouse
  • Ubiquitin-Protein Ligases
  • rhoA GTP-Binding Protein