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Membrane Tension Gates ERK-Mediated Regulation of Pluripotent Cell Fate.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

De Belly, Henry 
Stubb, Aki 
Yanagida, Ayaka 
Labouesse, Céline 
Jones, Philip H 

Abstract

Cell fate transitions are frequently accompanied by changes in cell shape and mechanics. However, how cellular mechanics affects the instructive signaling pathways controlling cell fate is poorly understood. To probe the interplay between shape, mechanics, and fate, we use mouse embryonic stem cells (ESCs), which change shape as they undergo early differentiation. We find that shape change is regulated by a β-catenin-mediated decrease in RhoA activity and subsequent decrease in the plasma membrane tension. Strikingly, preventing a decrease in membrane tension results in early differentiation defects in ESCs and gastruloids. Decreased membrane tension facilitates the endocytosis of FGF signaling components, which activate ERK signaling and direct the exit from the ESC state. Increasing Rab5a-facilitated endocytosis rescues defective early differentiation. Thus, we show that a mechanically triggered increase in endocytosis regulates early differentiation. Our findings are of fundamental importance for understanding how cell mechanics regulates biochemical signaling and therefore cell fate.

Description

Keywords

Beta-catenin, Cell fate choice, Cell surface mechanics, ERK, Embryonic stem cells, Endocytosis, Membrane tension, mechanical signalling, pluripotency, Animals, Cell Differentiation, Embryonic Stem Cells, Endocytosis, Mice, Mouse Embryonic Stem Cells, Signal Transduction

Journal Title

Cell Stem Cell

Conference Name

Journal ISSN

1934-5909
1875-9777

Volume Title

28

Publisher

Elsevier BV
Sponsorship
European Research Council (772798)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (641639)
Wellcome Trust (203151/Z/16/Z)
European Research Council (820188)
Medical Research Council (MC_PC_12009)
Medical Research Council (MC_PC_17230)
Medical Research Council (MC_UU_00012/5)
This work was supported b\ the European Union¶s Hori]on 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 641639 (ITN Biopol, HdB and EKP), the Medical Research Council UK (MRC programme award MC_UU_12018/5, HdB and EKP), the Human Frontier Science Program (Young InvestigatorGrant RGY 66/2013 to EKP), the Leverhulme Trust (Prize in Biological Sciences to EKP), an ERC Consolidator Grant (CellFateTech, 772798, KC), a core support grant from the Wellcome Trust and Medical Research Council to the Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute (KJC). KJC is a Royal Society University Research Fellow.