Sato Akira, Khadka Deepak K, Liu Wei, Bharti Ritu, Runnels Loren W, Dawid Igor B, Habas Raymond
Department of Biochemistry, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson School of Medicine, Piscataway, NJ 08854, USA.
Development. 2006 Nov;133(21):4219-31. doi: 10.1242/dev.02590. Epub 2006 Oct 4.
Non-canonical Wnt signaling plays important roles during vertebrate embryogenesis and is required for cell motility during gastrulation. However, the molecular mechanisms of how Wnt signaling regulates modification of the actin cytoskeleton remain incompletely understood. We had previously identified the Formin homology protein Daam1 as an important link between Dishevelled and the Rho GTPase for cytoskeletal modulation. Here, we report that Profilin1 is an effector downstream of Daam1 required for cytoskeletal changes. Profilin1 interacted with the FH1 domain of Daam1 and was localized with Daam1 to actin stress fibers in response to Wnt signaling in mammalian cells. In addition, depletion of Profilin1 inhibited stress fiber formation induced by non-canonical Wnt signaling. Inhibition or depletion of Profilin1 in vivo specifically inhibited blastopore closure in Xenopus but did not affect convergent extension movements, tissue separation or neural fold closure. Our studies define a molecular pathway downstream of Daam1 that controls Wnt-mediated cytoskeletal reorganization for a specific morphogenetic process during vertebrate gastrulation.
非经典Wnt信号在脊椎动物胚胎发育过程中发挥重要作用，并且在原肠胚形成期间的细胞运动中是必需的。然而，Wnt信号如何调节肌动蛋白细胞骨架修饰的分子机制仍未完全了解。我们之前已确定formin同源蛋白Daam1是Dishevelled与用于细胞骨架调节的Rho GTP酶之间的重要联系。在此，我们报道丝切蛋白1（Profilin1）是Daam1下游细胞骨架变化所需的效应器。Profilin1与Daam1的FH1结构域相互作用，并响应哺乳动物细胞中的Wnt信号与Daam1一起定位于肌动蛋白应力纤维。此外，Profilin1的缺失抑制了非经典Wnt信号诱导的应力纤维形成。体内Profilin1的抑制或缺失特异性地抑制了非洲爪蟾的胚孔闭合，但不影响汇聚延伸运动、组织分离或神经褶闭合。我们的研究定义了Daam1下游的一条分子途径，该途径控制脊椎动物原肠胚形成期间特定形态发生过程的Wnt介导的细胞骨架重组。
