Non-canonical Wnt signaling regulates junctional mechanocoupling during angiogenic collective cell migration
Non-canonical Wnt signaling regulates junctional mechanocoupling during angiogenic collective cell migration
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DOI：
10.7554/elife.45853
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发表时间：
2019-06-27
期刊：
影响因子：
7.7
通讯作者：
Franco, Claudio A.
中科院分区：
文献类型：
--
作者：
Carvalho, Joana R.;Fortunato, Isabela C.;Franco, Claudio A.
分级血管网络的形态发生依赖于内皮细胞（衬在血管内部的细胞）对多种生物力学信号的整合。血管网络的扩张是通过萌芽血管生成产生的，这是一个涉及广泛的细胞重排和集体细胞迁移的过程。然而，控制血管生成的集体行为的机制仍然知之甚少。在这里，我们表明这种集体细胞行为是由非经典的Wnt信号调节。我们确定Wnt 5a特异性激活ROR 2下游细胞连接处的Cdc 42，以加强粘附连接和肌动蛋白细胞骨架之间的偶联。我们表明，Wnt 5a信号稳定粘着斑蛋白结合α-连环蛋白，并废除粘着斑蛋白在体内和体外导致不协调的极性和缺陷的发芽小家鼠血管生成。我们的研究结果强调了非经典Wnt信号是如何通过微调内皮细胞之间的连接机械耦合来协调血管形态发生过程中的集体细胞行为的。
Morphogenesis of hierarchical vascular networks depends on the integration of multiple biomechanical signals by endothelial cells, the cells lining the interior of blood vessels. Expansion of vascular networks arises through sprouting angiogenesis, a process involving extensive cell rearrangements and collective cell migration. Yet, the mechanisms controlling angiogenic collective behavior remain poorly understood. Here, we show this collective cell behavior is regulated by non-canonical Wnt signaling. We identify that Wnt5a specifically activates Cdc42 at cell junctions downstream of ROR2 to reinforce coupling between adherens junctions and the actin cytoskeleton. We show that Wnt5a signaling stabilizes vinculin binding to alpha-catenin, and abrogation of vinculin in vivo and in vitro leads to uncoordinated polarity and deficient sprouting angiogenesis in Mus musculus. Our findings highlight how non-canonical Wnt signaling coordinates collective cell behavior during vascular morphogenesis by fine-tuning junctional mechanocoupling between endothelial cells.