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Peer-reviewedCC BYDevelopmental Cell

Tissue tension permits β-catenin phosphorylation to drive mesoderm specification in human embryonic stem cells

  • Nadia M.E. Ayad1,2,3,4
  • Aisha Almsoud5,2
  • Johnathon N. Lakins2,6
  • Ajinkya Ghagre7,8
  • Allen J. Ehrlicher8,2,9,10,11
  • Ophir D. Klein12
  • FuiBoon Kai5
  • Valerie Marie Weaver
12 affiliations
  1. 1Graduate 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
  2. 2Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
  3. 3Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 9443, USA
  4. 4Graduate Program in Bioengineering, University of California, San Francisco and University of California Berkeley, San Francisco, CA 9443, USA
  5. 5Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
  6. 6Department of Bioengineering, McGill University, Montreal, QC HA 0E9, Canada
  7. 7Department of Bioengineering, McGill University, Montreal, QC H3A 0E9, Canada
  8. 8Department of Bioengineering, Department of Anatomy and Cell Biology, Department of Biomedical Engineering, Department of Mechanical Engineering, Centre for Structural Biology, Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada
  9. 9Department of Bioengineering and Therapeutic Sciences, Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94143, USA
  10. 10Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
  11. 11UCSF Comprehensive Cancer Center, Helen Diller Family Cancer Research Center, University of California, San Francisco, San Francisco, CA 94143, USA
  12. 12Department of Pediatrics, Cedars-Sinai Guerin Children's, Los Angeles, CA 90048, USA
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Abstract

The role of morphogenetic forces in cell fate specification is an area of intense interest. Using an ectopically expressed nonphosphorylatable mutant of β-catenin (Y654F) in human embryonic stem cell colonies, we provide evidence that impeding tension-dependent Src-mediated β-catenin phosphorylation compromises BMP4-driven Brachyury (T) expression. This impediment also disrupts the epithelial-to-mesenchymal transition essential for mesoderm specification. Mechanistically, the Y654F mutation prevents the translocation of the junctional and cytoskeletal pool of β-catenin to the nucleus. However, saturation of Wnt signaling with exogenous Wnt3a or the inhibition of GSK3β rescues mesoderm expression. These findings suggest that BMP4 initiates a force-dependent junctional β-catenin translocation upstream of both Wnt secretion and cytosolic Wnt/β-catenin stabilization to drive mesoderm specification. Ultimately, our work highlights the importance of force-dependent Wnt/β-catenin signaling in the self-organization of tissues during developmental processes, such as gastrulation, and emphasizes a role for fine-tuned molecular regulation of the Wnt signaling pathway.

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Cite

BibTeXRIS
BibTeX
@article{ayad2026tissue,
  title = {{Tissue tension permits β-catenin phosphorylation to drive mesoderm specification in human embryonic stem cells}},
  author = {Nadia M.E. Ayad and Aisha Almsoud and Johnathon N. Lakins and Ajinkya Ghagre and Allen J. Ehrlicher and Ophir D. Klein and FuiBoon Kai and Valerie Marie Weaver},
  journal = {Developmental Cell},
  year = {2026},
  month = jul,
  doi = {10.1016/j.devcel.2026.06.014},
  url = {https://doi.org/10.1016/j.devcel.2026.06.014},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Tissue tension permits β-catenin phosphorylation to drive mesoderm specification in human embryonic stem cells
AU  - Nadia M.E. Ayad
AU  - Aisha Almsoud
AU  - Johnathon N. Lakins
AU  - Ajinkya Ghagre
AU  - Allen J. Ehrlicher
AU  - Ophir D. Klein
AU  - FuiBoon Kai
AU  - Valerie Marie Weaver
PY  - 2026
DA  - 2026/07/13
JO  - Developmental Cell
DO  - 10.1016/j.devcel.2026.06.014
UR  - https://doi.org/10.1016/j.devcel.2026.06.014
AB  - The role of morphogenetic forces in cell fate specification is an area of intense interest. Using an ectopically expressed nonphosphorylatable mutant of β-catenin (Y654F) in human embryonic stem cell colonies, we provide evidence that impeding tension-dependent Src-mediated β-catenin phosphorylation compromises BMP4-driven Brachyury (T) expression. This impediment also disrupts the epithelial-to-mesenchymal transition essential for mesoderm specification. Mechanistically, the Y654F mutation prevents the translocation of the junctional and cytoskeletal pool of β-catenin to the nucleus. However, saturation of Wnt signaling with exogenous Wnt3a or the inhibition of GSK3β rescues mesoderm expression. These findings suggest that BMP4 initiates a force-dependent junctional β-catenin translocation upstream of both Wnt secretion and cytosolic Wnt/β-catenin stabilization to drive mesoderm specification. Ultimately, our work highlights the importance of force-dependent Wnt/β-catenin signaling in the self-organization of tissues during developmental processes, such as gastrulation, and emphasizes a role for fine-tuned molecular regulation of the Wnt signaling pathway.
SN  - 1534-5807
SN  - 1878-1551
ER  -