Ayad Nadia M E, Lakins Johnathon N, Ghagre Ajinkya, Ehrlicher Allen J, Weaver Valerie M
Graduate Program in Bioengineering, University of California, San Francisco and University of California Berkeley, San Francisco, CA 94143, USA; Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
bioRxiv. 2023 Jul 15:2023.07.14.549074. doi: 10.1101/2023.07.14.549074.
The role of morphogenetic forces in cell fate specification is an area of intense interest. Our prior studies suggested that the development of high cell-cell tension in human embryonic stem cells (hESC) colonies permits the Src-mediated phosphorylation of junctional β-catenin that accelerates its release to potentiate Wnt-dependent signaling critical for initiating mesoderm specification. Using an ectopically expressed nonphosphorylatable mutant of β-catenin (Y654F), we now provide direct evidence that impeding tension-dependent Src-mediated β-catenin phosphorylation impedes the expression of Brachyury (T) and the epithelial-to-mesenchymal transition (EMT) necessary for mesoderm specification. Addition of exogenous Wnt3a or inhibiting GSK3β activity rescued mesoderm expression, emphasizing the importance of force dependent Wnt signaling in regulating mechanomorphogenesis. Our work provides a framework for understanding tension-dependent β-catenin/Wnt signaling in the self-organization of tissues during developmental processes including gastrulation.
形态发生力在细胞命运特化中的作用是一个备受关注的领域。我们之前的研究表明，人类胚胎干细胞（hESC）集落中高细胞间张力的形成允许Src介导的连接蛋白β-连环蛋白磷酸化，从而加速其释放，增强对启动中胚层特化至关重要的Wnt依赖性信号传导。现在，我们使用异位表达的β-连环蛋白非磷酸化突变体（Y654F）提供了直接证据，即阻碍张力依赖性Src介导的β-连环蛋白磷酸化会阻碍Brachyury（T）的表达以及中胚层特化所需的上皮-间质转化（EMT）。添加外源性Wnt3a或抑制GSK3β活性可挽救中胚层表达，强调了力依赖性Wnt信号传导在调节机械形态发生中的重要性。我们的工作为理解发育过程（包括原肠胚形成）中组织自组织过程中张力依赖性β-连环蛋白/Wnt信号传导提供了一个框架。
