Division of Molecular Embryology, DKFZ-ZMBH Alliance, German Cancer Research Center, Im Neuenheimer Feld 581, Heidelberg, Germany.
Dev Cell. 2011 Mar 15;20(3):303-14. doi: 10.1016/j.devcel.2011.01.006.
The R-Spondin (Rspo) family of secreted Wnt modulators is involved in development and disease and holds therapeutic promise as stem cell growth factors. Despite growing biological importance, their mechanism of action is poorly understood. Here, we show that Rspo3 binds syndecan 4 (Sdc4) and that together they activate Wnt/PCP signaling. In Xenopus embryos, Sdc4 and Rspo3 are essential for two Wnt/PCP-driven processes-gastrulation movements and head cartilage morphogenesis. Rspo3/PCP signaling during gastrulation requires Wnt5a and is transduced via Fz7, Dvl, and JNK. Rspo3 functions by inducing Sdc4-dependent, clathrin-mediated endocytosis. We show that this internalization is essential for PCP signal transduction, suggesting that endocytosis of Wnt-receptor complexes is a key mechanism by which R-spondins promote Wnt signaling.
R-Spondin（Rspo）家族是分泌型 Wnt 调节剂，参与发育和疾病，作为干细胞生长因子具有治疗潜力。尽管具有越来越重要的生物学意义，但它们的作用机制仍不清楚。在这里，我们表明 Rspo3 与 syndecan 4（Sdc4）结合，它们共同激活 Wnt/PCP 信号。在非洲爪蟾胚胎中，Sdc4 和 Rspo3 对于两个 Wnt/PCP 驱动的过程——原肠胚运动和头部软骨形态发生是必需的。原肠胚运动过程中的 Rspo3/PCP 信号需要 Wnt5a，并通过 Fz7、Dvl 和 JNK 转导。Rspo3 通过诱导 Sdc4 依赖性网格蛋白介导的内吞作用发挥功能。我们表明，这种内化对于 PCP 信号转导是必不可少的，这表明 Wnt-受体复合物的内吞作用是 R-spondin 促进 Wnt 信号的关键机制。
