PDGF α-receptor signal strength controls an RTK rheostat that integrates phosphoinositol 3′-kinase and phospholipase Cγ pathways during oligodendrocyte maturation

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

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

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 P13K pathway is required for PDGFRα-induced migration, whereas activation of both P13K and PLCγ are required for PDGFRα-induced proliferation. For proliferation, P13K activation is required at low ligand concentration, whereas PLCγ is required at high signal strength. Dose-response studies further demonstrate that PDGFRα activates P13K 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.

Original languageEnglish (US)
Pages (from-to)3499-3508
Number of pages10
JournalJournal of Neuroscience
Volume25
Issue number14
DOIs
StatePublished - Apr 6 2005

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Keywords

  • Development
  • Glia
  • Growth factor
  • Myelin
  • Oligodendrocyte
  • PDGF α-receptor
  • RTK
  • Signal transduction

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