Journal
JOURNAL OF NEUROSCIENCE
Volume 25, Issue 14, Pages 3499-3508Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5049-04.2005
Keywords
development; glia; growth factor; myelin; oligodendrocyte; PDGF alpha-receptor; RTK; signal transduction
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Funding
- NIMH NIH HHS [R01 MH054652, MH54652] Funding Source: Medline
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Receptors with tyrosine kinase activity (RTKs) control tissue growth and development in metazoans. How they generate cell-specific responses remains essentially unknown; one model proposes that distinct RTKs activate different second-messenger pathways, whereas a second proposes that all RTKs deliver a generic go signal to these pathways that is uniquely interpreted by downstream, cell-specific response competence factors. We examine pathway activation and pathway-specific responses downstream of PDGF alpha receptors, whose expression in the developing CNS identifies oligodendrocyte progenitor cells (OPCs) and whose activation controls OPC proliferation, migration, survival, and maturation. PDGFR-null mice die in utero, and OPCs that emerge before their demise have migration and proliferation defects and rapidly differentiate into postmitotic oligodendrocytes in vitro. OPCs from hemizygous mice also undergo precocious differentiation, indicating a role for PDGFR alpha gene dosage in timing OPC maturation. The rescue of PDGFR alpha-null OPCs with PDGFR alpha transgenes revealed specific roles for the phosphatidylinositol 3-kinase (PI3K) and phospholipase C gamma(PLC gamma) pathways and a distinct ligand concentration dependence. Activation of the PI3K pathway is required for PDGFR alpha-induced migration, whereas activation of both PI3K and PLC gamma are required for PDGFR alpha-induced proliferation. For proliferation, PI3K activation is required at low ligand concentration, whereas PLC gamma is required at high signal strength. Dose-response studies further demonstrate that PDGFR alpha activates PI3K at low ligand concentrations, whereas PLC gamma is activated at high signal strength. Thus, PDGFR alpha signaling acts like a rheostat rather than generic ON switch, with signal strength dictating pathway activation during OPC maturation.
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