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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Distinct effectors of platelet-derived growth factor receptor-α signaling are required for cell survival during embryogenesis
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Distinct effectors of platelet-derived growth factor receptor-α signaling are required for cell survival during embryogenesis

机译：血小板生成生长因子受体-α信号转导的不同效应子是胚胎发生过程中细胞存活所必需的

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摘要

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 meso-derm cells to lose direction and undergo apoptosis through the mitochondria! 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 phospho-lipase 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.
机译：血小板衍生的生长因子受体（PDGFR）信号对于许多生物（包括青蛙，小鼠，斑马鱼和海胆）的正常胚胎发育至关重要。然而，人们对PDGFR信号在早期发育过程中的作用方式知之甚少，这主要是因为通过PDGFRα或PDGFRβ抑制信号传递具有胚胎致死性。在非洲爪蟾胚胎中，PDGFRα信号的破坏会导致前中皮细胞的迁移失去方向，并通过线粒体发生凋亡！途径。为了了解PDGFRα在此过程中的功能机制，我们已经分析了体内所有已知的效应子结合位点。通过使用二聚化的化学诱导剂激活嵌合PDGFRα，我们已经确定了磷脂酶Cγ（PLCγ）在保护细胞免于死亡中的作用。 PDGFRα介导的细胞存活需要PLCγ和磷脂酰肌醇3激酶信号转导，而具有这两个信号转导因子结合位点的PDGFRα足以实现这种活性。此过程不需要PDGFRα信号传导的其他效应子Shf，SHP-2和Crk。因此，我们的发现表明，通过PLCγ和磷脂酰肌醇3-激酶的PDGFRα信号传导在预防早期发育中的凋亡方面具有保护作用。此外，我们证明了二聚化的小分子诱导剂提供了强大的系统来操纵发育中的胚胎中的受体功能。

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