Plakoglobin is a mechanoresponsive regulator of naive pluripotency

Timo N. Kohler, Joachim Jonghe, Anna L. Ellermann, Ayaka Yanagida, Michael Herger, Erin M. Slatery, Antonia Weberling, Clara Munger, Katrin Fischer, Carla Mulas, Alex Winkel, Connor Ross, Sophie Bergmann, Kristian Franze, Kevin Chalut, Jennifer Nichols, Thorsten E. Boroviak () and Florian Hollfelder ()
Additional contact information
Timo N. Kohler: University of Cambridge
Joachim Jonghe: University of Cambridge
Anna L. Ellermann: University of Cambridge
Ayaka Yanagida: University of Cambridge, Jeffrey Cheah Biomedical Centre
Michael Herger: University of Cambridge
Erin M. Slatery: University of Cambridge
Antonia Weberling: University of Cambridge
Clara Munger: University of Cambridge
Katrin Fischer: University of Cambridge
Carla Mulas: University of Cambridge, Jeffrey Cheah Biomedical Centre
Alex Winkel: University of Cambridge
Connor Ross: University of Cambridge, Jeffrey Cheah Biomedical Centre
Sophie Bergmann: University of Cambridge
Kristian Franze: University of Cambridge
Kevin Chalut: University of Cambridge, Jeffrey Cheah Biomedical Centre
Jennifer Nichols: University of Cambridge, Jeffrey Cheah Biomedical Centre
Thorsten E. Boroviak: University of Cambridge, Jeffrey Cheah Biomedical Centre
Florian Hollfelder: University of Cambridge

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Biomechanical cues are instrumental in guiding embryonic development and cell differentiation. Understanding how these physical stimuli translate into transcriptional programs will provide insight into mechanisms underlying mammalian pre-implantation development. Here, we explore this type of regulation by exerting microenvironmental control over mouse embryonic stem cells. Microfluidic encapsulation of mouse embryonic stem cells in agarose microgels stabilizes the naive pluripotency network and specifically induces expression of Plakoglobin (Jup), a vertebrate homolog of β-catenin. Overexpression of Plakoglobin is sufficient to fully re-establish the naive pluripotency gene regulatory network under metastable pluripotency conditions, as confirmed by single-cell transcriptome profiling. Finally, we find that, in the epiblast, Plakoglobin was exclusively expressed at the blastocyst stage in human and mouse embryos – further strengthening the link between Plakoglobin and naive pluripotency in vivo. Our work reveals Plakoglobin as a mechanosensitive regulator of naive pluripotency and provides a paradigm to interrogate the effects of volumetric confinement on cell-fate transitions.

Date: 2023
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DOI: 10.1038/s41467-023-39515-0

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