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

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 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.

Initiation of Oligodendrocyte Progenitor Cell Migration by a PDGF-A Activated Extracellular Regulated Kinase (ERK) Signaling Pathway

“…Contrary to our conclusion, McKinnon et al reported a role for PI 3 K in the regulation of OP migration [40]. They assessed the migration of OP away from spinal cord explants to show that PDGFRα defective cells could be rescued with transgenic PDGFRα.…”

“…In their study, if the transgene was PI 3 K activation-defective, OP cells did not migrate. An explanation for these contradictory results may be that we only expose the cells to PDGF-A for 30 min, whereas McKinnon and colleagues used PDGF-A to maintain their cultures for several days prior to the assay, withdrawing PDGF-A preceding initiation of the experiment [40]. PDGF induces proliferation after 8 h exposure of the cells to the mitogen [37] and may also result in activation of other intracellular pathways that may alter the PI 3 K dependence.…”

“…It is our hypothesis that short term exposure to PDGF-A activates only the migratory activity of OP. Accordingly, longer term exposure of 8 h or more is required for the activation of other intracellular pathways leading to proliferation, such as PI 3 K [4,40].…”

Platelet derived growth factor B gene expression in the Xenopus laevis developing central nervous system

“…These data established the presence of pdgf-b mRNA within precise and confined areas of the developing CNS, suggesting a potential role for pdgf-b in CNS development. This idea is supported also by previous data showing that the activity of the PDGF pathway is necessary to properly regulate oligodendrocyte progenitor cells (OPC) migration and proliferation (McKinnon et al, 2005) and that pdgf-b overexpression in vitro is sufficient to induce an OPC identity in neural progenitor cells (Appolloni et al, 2009). In addition, mutations in PDGF-B gene are responsible for causing primary familial brain calcification disease in humans (Keller et al, 2013).…”

The PDGFC CUB Domain Enhances Survival in PDGFC Mutant Mice

“…Likewise, the severity of abnormalities in targeted pdgfrα null mice varies depending on background, with only DBA mice surviving until birth [1,39]. Though our observations may be due in part to strain differences, pdgfc tm1lex and pdgfc tm1nagy mice appear to have different viabilities and phenotypes.…”