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The Journal of Neuroscience, June 15, 2000, 20(12):4635-4645
Axonal Regulation of Schwann Cell Proliferation and Survival and
the Initial Events of Myelination Requires PI 3-Kinase Activity
Patrice
Maurel1 and
James
L.
Salzer1, 2, 3
Departments of 1 Cell Biology, 2 Neurology,
and the 3 Kaplan Cancer Center, New York University Medical
Center, New York, New York 10016
In this report, we have investigated the signaling pathways that
are activated by, and mediate the effects of, the neuregulins and
axonal contact in Schwann cells. Phosphatidylinositol 3-kinase (PI
3-kinase) and mitogen-activated protein kinase kinase (MAPK kinase) are strongly activated in Schwann cells by glial growth factor
(GGF), a soluble neuregulin, and by contact with neurite membranes;
both kinase activities are also detected in Schwann cell-DRG neuron
cocultures. Inhibition of the PI 3-kinase, but not the MAP
kinase, pathway reversibly inhibited Schwann cell proliferation
induced by GGF and neurites. Cultured Schwann cells undergo apoptosis
after serum deprivation and can be rescued by GGF or contact with
neurites; these survival effects were also blocked by inhibition of PI
3-kinase. Finally, we have examined 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 myelination but did not affect
laminin deposition. Later, after Schwann cells established a one-to-one
relationship with axons, inhibition of PI 3-kinase did not block myelin
formation, but the myelin sheaths that formed were shorter, and the
rate of myelin protein accumulation was markedly decreased. PI 3-kinase inhibition had no observable effect on the maintenance of myelin sheaths in mature myelinated cocultures. These results indicate that
activation of PI 3-kinase by axonal factors, including the neuregulins,
promotes Schwann cell proliferation and survival and implicate PI
3-kinase in the early events of myelination.
Key words:
Schwann cell; PI 3-kinase; MAP kinase; proliferation; survival; myelination; signaling pathways
Copyright © 2000 Society for Neuroscience 0270-6474/00/20124635-11$05.00/0
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