Tissue tension permits β-catenin phosphorylation to drive mesoderm specification in human embryonic stem cells.
Nadia M E AyadJohnathon N LakinsAjinkya GhagreAllen J EhrlicherValerie M WeaverPublished in: bioRxiv : the preprint server for biology (2023)
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.
Keyphrases
- cell fate
- pluripotent stem cells
- embryonic stem cells
- epithelial mesenchymal transition
- cell proliferation
- endothelial cells
- poor prognosis
- signaling pathway
- stem cells
- single cell
- cell therapy
- tyrosine kinase
- protein kinase
- induced pluripotent stem cells
- gene expression
- binding protein
- mesenchymal stem cells
- bone marrow