PDGF α-Receptor Signal Strength Controls an RTK Rheostat That Integrates Phosphoinositol 3′-Kinase and Phospholipase Cγ Pathways during Oligodendrocyte Maturation

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