Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development
Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development
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DOI：
10.7554/elife.47300
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发表时间：
2019-06-21
期刊：
影响因子：
7.7
通讯作者：
Nathans, Jeremy
中科院分区：
文献类型：
--
作者：
Cho, Chris;Wang, Yanshu;Nathans, Jeremy
wnt -卷曲特异性的分子基础是发育生物学中的一个核心问题。Reck是一种多结构域、多功能的糖基磷脂酰肌醇锚定蛋白，通过Wnt7a和Wnt7b与7-跨膜蛋白Gpr124合作，特异性增强β -catenin信号传导。在区分Wnt7a和Wnt7b与其他wnt的氨基酸中，有两个簇对于以依赖Reck和gpr124的方式进行信号传导至关重要。两个簇都远离卷曲结合的位置：一个位于氨基末端，另一个位于突出的环中。在Reck中，含有6个半胱氨酸的异常结构域（CC结构域）的5个串联重复序列中的第4个对Wnt7a刺激至关重要：CC4中的P256A和W261A的替换消除了这种活性，而不会改变蛋白质的丰富度或表面定位。携带Reck（P256A,W261A）的小鼠胚胎前脑血管生成存在严重缺陷，这为Reck通过特异性刺激Wnt7a和Wnt7b信号通路促进中枢神经系统血管生成提供了迄今为止最有力的证据。
The molecular basis of Wnt-Frizzled specificity is a central question in developmental biology. Reck, a multi-domain and multi-functional glycosylphosphatidylinositol-anchored protein, specifically enhances beta-catenin signaling by Wnt7a and Wnt7b in cooperation with the 7-transmembrane protein Gpr124. Among amino acids that distinguish Wnt7a and Wnt7b from other Wnts, two clusters are essential for signaling in a Reck- and Gpr124-dependent manner. Both clusters are far from the site of Frizzled binding: one resides at the amino terminus and the second resides in a protruding loop. Within Reck, the fourth of five tandem repeats of an unusual domain with six-cysteines (the CC domain) is essential for Wnt7a stimulation: substitutions P256A and W261A in CC4 eliminate this activity without changing protein abundance or surface localization. Mouse embryos carrying Reck(P256A,W261A) have severe defects in forebrain angiogenesis, providing the strongest evidence to date that Reck promotes CNS angiogenesis by specifically stimulating Wnt7a and Wnt7b signaling.