PDGF alpha-receptor signal strength controls an RTK rheostat that integrates phosphoinositol 3'-kinase and phospholipase Cgamma 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 PDGFalpha receptors, whose expression in the developing CNS identifies oligodendrocyte progenitor cells (OPCs) and whose activation controls OPC proliferation, migration, survival, and maturation. PDGFRalpha-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 PDGFRalpha gene dosage in timing OPC maturation. The rescue of PDGFRalpha-null OPCs with PDGFRalpha transgenes revealed specific roles for the phosphatidylinositol 3-kinase (PI3K) and phospholipase Cgamma (PLCgamma) pathways and a distinct ligand concentration dependence. Activation of the PI3K pathway is required for PDGFRalpha-induced migration, whereas activation of both PI3K and PLCgamma are required for PDGFRalpha-induced proliferation. For proliferation, PI3K activation is required at low ligand concentration, whereas PLCgamma is required at high signal strength. Dose-response studies further demonstrate that PDGFRalpha activates PI3K at low ligand concentrations, whereas PLCgamma is activated at high signal strength. Thus, PDGFRalpha signaling acts like a rheostat rather than generic ON switch, with signal strength dictating pathway activation during OPC maturation.
McKinnon
Randall D
RD
Department of Surgery (Neurosurgery), University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA. mckinnon@umdnj.edu
Waldron
Sean
S
Kiel
Mary E
ME
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000941:Antigens / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005732:Gangliosides / Q000378:metabolism; D018014:Gene Transfer Techniques; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008967:Molecular Biology / Q000379:methods; D016296:Mutagenesis / Q000502:physiology; D004676:Myelin Basic Protein / Q000378:metabolism; D019081:O Antigens / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism*; D010766:Phosphorylation; D011509:Proteoglycans / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000172:deficiency / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D000099216:Chondroitin Sulfate Proteoglycan 4
D000941:Antigens; D005732:Gangliosides; D008565:Membrane Proteins; D004676:Myelin Basic Protein; D019081:O Antigens; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D011509:Proteoglycans; D020794:Receptor Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D012694:Serine; D014443:Tyrosine; D000099216:Chondroitin Sulfate Proteoglycan 4; C430944:O4 antigen, Stenotrophomonas; C062875:ganglioside A2B5