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

Cell fate transitions are frequently accompanied by changes in cell shape and mechanics. Yet how cellular mechanics affects the instructive signalling pathways controlling cell fate is poorly understood. To probe the interplay between shape, mechanics, and fate, we use mouse embryonic stem (ES) cells, which change shape as they undergo early differentiation. We find that shape change is regulated by a E-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 ES cells and gastruloids. Decreased membrane tension facilitates endocytosis of FGF signaling components, which activates ERK signaling and directs exit from the ES cell 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.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