Membrane Tension Gates ERK-Mediated Regulation of Pluripotent Cell Fate

• Published in: Cell stem cell Vol. 28; no. 2; pp. 273 - 284.e6
• Main Authors: De Belly, Henry, Stubb, Aki, Yanagida, Ayaka, Labouesse, Céline, Jones, Philip H., Paluch, Ewa K., Chalut, Kevin J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.02.2021; Cell Press
• Subjects: Animals; Beta-catenin; Cell Differentiation; Cell fate choice; Cell surface mechanics; Embryonic Stem Cells; Endocytosis; ERK; mechanical signalling; Membrane tension; Mice; Mouse Embryonic Stem Cells; pluripotency; Signal Transduction; Cell surface mechanics; Endocytosis; mechanical signalling; Beta-catenin; Membrane tension; pluripotency; Embryonic stem cells; Cell fate choice; ERK
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2020.10.018

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. [Display omitted] •Membrane tension decreases in early differentiation of embryonic stem cells•Membrane tension drop leads to increase in endocytic ERK signaling and fate transition•Membrane tension drop initiated by regulatory axis, including β-catenin, RhoA, and ERM•Preventing membrane tension drop results in developmental defects In this study, Chalut and colleagues investigate how changes in cell surface mechanics drive early differentiation in embryonic stem cells and show that preventing this change leads to developmental defects. They identify a membrane tension gated increase in endocytosis as a key mechanism regulating an ERK-regulated cell fate transition.