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The Journal of Neuroscience, April 6, 2005, 25(14):3499-3508; doi:10.1523/JNEUROSCI.5049-04.2005

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Cellular/Molecular
PDGF -Receptor Signal Strength Controls an RTK Rheostat That Integrates Phosphoinositol 3'-Kinase and Phospholipase C Pathways during Oligodendrocyte Maturation

Randall D. McKinnon, Sean Waldron, and Mary E. Kiel

Department of Surgery (Neurosurgery), University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

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 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 gene dosage in timing OPC maturation. The rescue of PDGFR-null OPCs with PDGFR transgenes revealed specific roles for the phosphatidylinositol 3-kinase (PI3K) and phospholipase C (PLC) pathways and a distinct ligand concentration dependence. Activation of the PI3K pathway is required for PDGFR-induced migration, whereas activation of both PI3K and PLC are required for PDGFR-induced proliferation. For proliferation, PI3K activation is required at low ligand concentration, whereas PLC is required at high signal strength. Dose-response studies further demonstrate that PDGFR activates PI3K at low ligand concentrations, whereas PLC is activated at high signal strength. Thus, PDGFR signaling acts like a rheostat rather than generic ON switch, with signal strength dictating pathway activation during OPC maturation.

Key words: development; glia; growth factor; myelin; oligodendrocyte; PDGF -receptor; RTK; signal transduction

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Received Oct 1, 2004; revised February 16, 2005; accepted February 18, 2005.

This article has been cited by other articles:

				R. Chittajallu, A. A. Aguirre, and V. Gallo Downregulation of Platelet-Derived Growth Factor-{alpha} Receptor-Mediated Tyrosine Kinase Activity as a Cellular Mechanism for K+-Channel Regulation during Oligodendrocyte Development In Situ J. Neurosci., September 21, 2005; 25(38): 8601 - 8610. [Abstract] [Full Text] [PDF]

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