Distinct effectors of platelet-derived growth factor receptor-α signaling are required for cell survival during embryogenesis

Abstract

Platelet-derived growth factor receptor (PDGFR) signaling is essential for normal embryonic development in many organisms, including frog, mouse, zebrafish, and sea urchin. The mode of action of PDGFR signaling during early development is poorly understood, however, mostly because inhibition of signaling through either the PDGFR alpha or PDGFR beta is embryonic lethal. In Xenopus embryos, disruption of PDGFR alpha signaling causes migrating anterior mesoderm cells to lose direction and undergo apoptosis through the mitochondrial pathway. To understand the mechanism of PDGFRa function in this process, we have analyzed all known effector-binding sites in vivo. By using a chemical inducer of dimerization to activate chimera PDGFR alpha s, we have identified a role for phospholipase C gamma (PLC gamma) in protecting cells from death, PDGFR alpha-mediated cell survival requires PLC gamma and phosphaticlylinositol 3-kinase signaling, and that PDGFR alpha with binding sites for these two signaling factors is sufficient for this activity. Other effectors of PDGFR alpha signaling, Shf, SHP-2, and Crk, are not required for this process. Thus, our findings show that PDGFR alpha signaling through PLC gamma and phosphatidylinositol 3-kinase has a protective role in preventing apoptosis in early development. Furthermore, we demonstrate that small molecule inducers of dimerization provide a powerful system to manipulate receptor function in developing embryos.