Enteric neuroblasts require the phosphatidylinositol 3-kinase/Akt/Forkhead pathway for GDNF-stimulated survival

Mol Cell Neurosci. 2005 May;29(1):107-19. doi: 10.1016/j.mcn.2005.02.005.


Glial cell line-derived neurotrophic factor (GDNF)/Ret signaling is required for enteric neural crest survival, proliferation, migration and process extension, but signaling pathways that mediate enteric nervous system (ENS) precursor development are poorly understood. We therefore examined GDNF effects on immunoselected ENS precursor survival and neuronal process extension in the presence of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathway inhibitors. These studies demonstrated that GDNF promotes ENS precursor survival through phosphatidylinositol-3-kinase. Specifically, GDNF induces phosphorylation of Akt and loss of the Akt substrates FOXO1 and FOXO3a from the nucleus of ENS precursors. Furthermore, dominant negative Akt or active FOXO1 constructs promote ENS precursor cell death while a dominant negative FOXO1 construct prevents cell death. In contrast, the MAPK kinase inhibitor PD98059 did not influence ENS precursor survival or neurite extension. These data demonstrate a critical role for PI-3 kinase/Akt/FOXO signaling, but not for MAPK in ENS precursor survival and neurite extension.

Publication types

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

MeSH terms

  • Animals
  • Cell Death / physiology
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Enteric Nervous System / cytology*
  • Enteric Nervous System / metabolism
  • Forkhead Transcription Factors
  • Glial Cell Line-Derived Neurotrophic Factor
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Nerve Growth Factors / pharmacology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurites / drug effects
  • Neurites / enzymology
  • Neurons / cytology
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Nerve Growth Factor / metabolism
  • Stem Cells / drug effects
  • Stem Cells / enzymology*
  • Stem Cells / ultrastructure
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transfection


  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Gdnf protein, rat
  • Glial Cell Line-Derived Neurotrophic Factor
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Proto-Oncogene Proteins
  • Receptor, Nerve Growth Factor
  • Transcription Factors
  • Foxo1 protein, rat
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt