NRP1 Regulates CDC42 Activation to Promote Filopodia Formation in Endothelial Tip Cells.
NRP1 Regulates CDC42 Activation to Promote Filopodia Formation in Endothelial Tip Cells.
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DOI：
10.1016/j.celrep.2015.05.018
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发表时间：
2015-06-16
期刊：
影响因子：
8.8
通讯作者：
Ruhrberg C
中科院分区：
文献类型：
--
作者：
Fantin A;Lampropoulou A;Gestri G;Raimondi C;Senatore V;Zachary I;Ruhrberg C
血管萌芽是由布满丝状伪足的内皮尖端细胞引导的，这些细胞对血管生成信号做出反应。马赛克谱系追踪此前表明，NRP 1对于尖端细胞功能至关重要，尽管其在尖端细胞中的机制作用仍然不清楚。在这里，我们表明，NRP1的遗传尖端细胞的身份。相反，我们发现，NRP1是必不可少的，以形成丝状伪足的爆发，区分尖端细胞形态从邻近的柄细胞，因为它使细胞外基质（ECM）诱导的活化CDC 42，丝状伪足形成的关键调节。因此，NRP1敲除和药理学CDC42抑制类似地损害了体外和体内发育中的斑马鱼的丝状伪足形成。在小鼠视网膜血管生成过程中，CDC42抑制损害了尖端细胞和血管网络的形成，导致类似于由于ECM诱导而不是VEGF诱导的NRP1信号传导丧失而导致的缺陷。我们的结论是，NRP1使ECM诱导的丝状伪足形成的尖端细胞的功能，在萌芽血管生成。NRP1使内皮尖端细胞的形态学而非遗传学特化NRP1是基质诱导的内皮细胞中的CDC 42活化所必需的NRP1通过CDC 42促进丝状伪足延伸和肌动蛋白重塑内皮NRP1损失和CDC 42抑制类似地损害血管生成在血管生成期间，新的血管芽由丝状伪足镶嵌的尖端细胞引导以感知环境信号并使定向迁移成为可能。NRP1是一种感受血管生成信号的尖端细胞蛋白。Fantin等人现在表明，NRP1通过激活CDC 42促进丝状伪足形成和肌动蛋白重塑来促进尖端细胞功能。
Sprouting blood vessels are led by filopodia-studded endothelial tip cells that respond to angiogenic signals. Mosaic lineage tracing previously revealed that NRP1 is essential for tip cell function, although its mechanistic role in tip cells remains poorly defined. Here, we show that NRP1 is dispensable for genetic tip cell identity. Instead, we find that NRP1 is essential to form the filopodial bursts that distinguish tip cells morphologically from neighboring stalk cells, because it enables the extracellular matrix (ECM)-induced activation of CDC42, a key regulator of filopodia formation. Accordingly, NRP1 knockdown and pharmacological CDC42 inhibition similarly impaired filopodia formation in vitro and in developing zebrafish in vivo. During mouse retinal angiogenesis, CDC42 inhibition impaired tip cell and vascular network formation, causing defects that resembled those due to loss of ECM-induced, but not VEGF-induced, NRP1 signaling. We conclude that NRP1 enables ECM-induced filopodia formation for tip cell function during sprouting angiogenesis. NRP1 enables morphological, but not genetic, specialization of endothelial tip cells NRP1 is essential for matrix-induced CDC42 activation in endothelial cells NRP1 promotes filopodia extension and actin remodeling via CDC42 Endothelial NRP1 loss and CDC42 inhibition similarly impair angiogenesis During angiogenesis, new blood vessel sprouts are led by filopodia-studded tip cells to sense environmental signals and enable directional migration. NRP1 is a tip cell protein that senses angiogenic cues. Fantin et al. now show that NRP1 promotes tip cell function by enabling CDC42 activation for filopodia formation and actin remodeling.