title: Enteric neuroblasts require the phosphatidylinositol 3-kinase/Akt/Forkhead pathway for GDNF-stimulated survival.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Digestive Diseases, Emory University, 615 Michael Street, Whitehead Research Building, Suite 246, Atlanta, GA 30322, USA. ssrini2@emory.edu
authors.forename: Shanthi
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Mallappa
authors.initials: M
authors.lastname: Anitha
authors.forename: Simon
authors.initials: S
authors.lastname: Mwangi
authors.forename: Robert O
authors.initials: RO
authors.lastname: Heuckeroth
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017615:Enteric Nervous System / Q000166:cytology* / Q000378:metabolism; D051858:Forkhead Transcription Factors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D009414:Nerve Growth Factors / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000201:enzymology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000071161:Forkhead Box Protein O1
chemical_list: D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020800:Receptor, Nerve Growth Factor; D014157:Transcription Factors; C495041:Gdnf protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C494920:Akt1 protein, rat