Enteric neuroblasts require the phosphatidylinositol 3-kinase pathway for GDNF-stimulated proliferation

The enteric nervous system (ENS) develops from neural crest cells that ente r the gut, migrate, proliferate, and differentiate into neurons and glia, T he growth factor glial-derived neurotrophic factor (GDNF) stimulates the pr oliferation and survival of enteric crest-derived cells. We investigated th e intracellular signaling pathways activated by GDNF and their involvement in proliferation. We found that GDNF stimulates the phosphorylation of both the PI 3-kinase downstream substrate Akt and the MAP kinase substrate ERK in cultures of immunoaffinity-purified embryonic avian enteric crest-derive d cells. The selective PI 3-kinase inhibitor LY-294002 blocked GDNF-stimula ted Akt phosphorylation in purified crest cells, and reduced proliferation in cultures of dissociated quail gut. The ERK kinase (MEK) inhibitors PD 98 059 and UO126 did not reduce GDNF-stimulated proliferation, although PD 980 59 blocked GDNF-stimulated phosphorylation of ERK. We conclude that the PI 3-kinase pathway is necessary for the GDNF-stimulated proliferation of ente ric neuroblasts. (C) 2001 John Wiley & Sons, Inc.