Axonal regulation of Schwann cell proliferation and survival and the initial events of myelination requires PI 3-kinase activity

In this report, we have investigated the signaling pathways that are activa ted by, and mediate the effects of, the neuregulins and axonal contact in S chwann cells. Phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activ ated protein kinase kinase (MAPK kinase) are strongly activated in Schwann cells by glial growth factor (GGF), a soluble neuregulin, and by contact wi th neurite membranes; both kinase activities are also detected in Schwann c ell-DRG neuron cocultures. Inhibition of the PI 3-kinase, but not the MAP k inase, pathway reversibly inhibited Schwann cell proliferation induced by G GF and neurites. Cultured Schwann cells undergo apoptosis after serum depri vation and can be rescued by GGF or contact with neurites; these survival e ffects were also blocked by inhibition of PI 3-kinase. Finally, we have exa mined the role of these signaling pathways in Schwann cell differentiation in cocultures. At early stages of coculture, inhibition of PI 3-kinase, but not MAPK kinase, blocked Schwann cell elongation and subsequent myelinatio n but did not affect laminin deposition. Later, after Schwann cells establi shed a one-to-one relationship with axons, inhibition of PI 3-kinase did no t block myelin formation, but the myelin sheaths that formed were shorter, and the rate of myelin protein accumulation was markedly decreased. PI 3-ki nase inhibition had no observable effect on the maintenance of myelin sheat hs in mature myelinated cocultures. These results indicate that activation of PI 3-kinase by axonal factors, including the neuregulins, promotes Schwa nn cell proliferation and survival and implicate PI 3-kinase in the early e vents of myelination.