Dickkopf-1 regulates gastrulation movements by coordinated modulation of Wnt/βcatenin and Wnt/PCP activities, through interaction with the Dally-like homolog Knypek
Dickkopf-1 regulates gastrulation movements by coordinated modulation of Wnt/βcatenin and Wnt/PCP activities, through interaction with the Dally-like homolog Knypek
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DOI：
10.1101/gad.406007
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发表时间：
2007-02-15
影响因子：
10.5
通讯作者：
Houart, Corinne
中科院分区：
文献类型：
--
作者：
Caneparo, Luca;Huang, Ya-Lin;Houart, Corinne
Dickkopf-1（Dkk 1）是一种分泌性蛋白质，负调节Wnt/β连环蛋白途径。缺乏Dkk 1功能会影响青蛙和小鼠的头部形成，这支持了Dkk 1在原肠胚形成过程中充当“头部诱导物”的观点。我们在这里表明，缺乏Dkk 1功能加速内化和吻进展的中内胚层和功能的增益减慢内化和收敛扩展，表明Dkk 1在调节这些运动的新作用。在变形子中发现的运动表型在Wnt/β连环蛋白途径过度激活的胚胎中没有观察到，并且显性阴性Wnt蛋白不能挽救由Dkk 1缺失诱导的原肠胚形成运动缺陷。这些数据有力地表明，Dkk 1是在β连环蛋白独立的方式时，调节原肠胚运动。我们证明了磷脂酰肌醇蛋白聚糖4/6同源物Knypek（Kny）与Dkk 1结合，并且它们能够在体内功能性相互作用。此外，Dkk 1对原肠胚形成运动的调节是kny依赖性的。Kny是Wnt/平面细胞极性（PCP）通路的一个组成部分。我们发现Dkk 1确实能够在爪蟾和斑马鱼中激活这一通路。此外，β连环蛋白和PCP活性的伴随改变能够模拟吗啡肽加速细胞运动表型。因此，我们的数据表明，Dkk 1通过与LRP 5/6和Kny的相互作用以及Wnt/β连环蛋白和Wnt/PCP途径的协调调节来调节原肠胚形成运动。
Dickkopf-1 (Dkk1) is a secreted protein that negatively modulates the Wnt/beta catenin pathway. Lack of Dkk1 function affects head formation in frog and mice, supporting the idea that Dkk1 acts as a "head inducer" during gastrulation. We show here that lack of Dkk1 function accelerates internalization and rostral progression of the mesendoderm and that gain of function slows down both internalization and convergence extension, indicating a novel role for Dkk1 in modulating these movements. The motility phenotype found in the morphants is not observed in embryos in which the Wnt/beta catenin pathway is overactivated, and that dominant-negative Wnt proteins are not able to rescue the gastrulation movement defect induced by absence of Dkk1. These data strongly suggest that Dkk1 is acting in a beta catenin independent fashion when modulating gastrulation movements. We demonstrate that the glypican 4/6 homolog Knypek (Kny) binds to Dkk1 and that they are able to functionally interact in vivo. Moreover, Dkk1 regulation of gastrulation movements is kny dependent. Kny is a component of the Wnt/planar cell polarity (PCP) pathway. We found that indeed Dkk1 is able to activate this pathway in both Xenopus and zebrafish. Furthermore, concomitant alteration of the beta catenin and PCP activities is able to mimic the morphant accelerated cell motility phenotype. Our data therefore indicate that Dkk1 regulates gastrulation movement through interaction with LRP5/6 and Kny and coordinated modulations of Wnt/beta catenin and Wnt/PCP pathways.