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 PDGFRα or PDGFRβ is embryonic lethal. In Xenopus embryos, disruption of PDGFRα signaling causes migrating anterior mesoderm cells to lose direction and undergo apoptosis through the mitochondrial pathway. To understand the mechanism of PDGFRα function in this process, we have analyzed all known effector-binding sites in vivo. By using a chemical inducer of dimerization to activate chimera PDGFRαs, we have identified a role for phospholipase Cγ (PLCγ) in protecting cells from death. PDGFRα-mediated cell survival requires PLCγ and phosphatidylinositol 3-kinase signaling, and that PDGFRα with binding sites for these two signaling factors is sufficient for this activity. Other effectors of PDGFRα signaling, Shf, SHP-2, and Crk, are not required for this process. Thus, our findings show that PDGFRα signaling through PLCγ 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.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- June 2005
- DOI:
- 10.1073/pnas.0502885102
- Bibcode:
- 2005PNAS..102.8233V
- Keywords:
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- DEVELOPMENTAL BIOLOGY