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Abstract

The mechanical properties of the cell surface are master regulators of various cell processes, ranging from shape determination, to migration, to fate acquisition. The surface of animal cells consists of the plasma membrane, the actomyosin cell cortex, and Membrane-to-Cortex Attachment (MCA), defined as the protein-mediated tethering of the plasma membrane to the cell cortex beneath. MCA has been shown to contribute to cell surface mechanics and to be involved in the regulation of different biological processes at the cell surface. However, MCA remains the most elusive element of the animal cell surface and there is a clear gap in our understanding of its roles and regulation. This is mainly due to the lack of proper methods to specifically perturb MCA in cells. In this thesis, I am going to describe my PhD work on MCA. In the first part of my PhD, I engineered and validated a molecular tool, named iMC linker, which allows to increase specifically MCA in cellular model systems. Next, With iMC linker at hand, we studied MCA from both a biological and a biophysical viewpoint. First, we focused on cell differentiation, a process already shown to be regulated by mechanical properties of the extracellular matrix and the cell surface. Using mouse embryonic stem cells as a model system, we found that cells need to reduce their MCA in order to differentiate. Preventing this reduction by expressing iMC linker, locks the cells in a state of naïve pluripotency. Therefore, we uncovered a novel role for MCA in regulating cell differentiation. Second, I will describe our current efforts in deciphering the biophysical contribution of MCA to the mechanical properties of the cell surface. Strikingly, we found that MCA regulates cell cortex mechanics. Specifically, an iMC linker- mediated increase in MCA is coupled with a reduction in cell cortex stiffness and cortical tension. The implication of these findings may be relevant for various cellular processes regulated by cortex mechanics, such as cytokinesis and cell fate acquisition.