Membrane tension as a long-range integrator of cell physiology

PROJECT SUMMARY Membrane tension is thought to be a long-range integrator of cell physiology. During migration, membrane tension has been proposed to enable cell polarity through front-back coordination and long-range protrusion competition. These roles necessitate effective tension transmission across the cell. However, it remains a source of significant debate as to whether cell membranes support or resist long-range membrane tension propagation. I speculated that this this discrepancy likely originates from the use of exogenous forces that may not accurately mimic endogenous forces. To overcome this complication, I used optogenetics to directly control localized actin-based protrusions or actomyosin contractions while simultaneously monitoring the propagation of membrane tension using dual-trap optical tweezers. My results led me to propose a unifying model of tension propagation in which actin-driven protrusions and actomyosin contractions both elicit rapid global membrane tension propagation, while forces applied to cell membranes alone do not. This work laid the foundations of my ongoing studies and raises many important questions. For some processes, membrane tension needs to act locally and in others, it needs to act at the range of the entire cell or multiple cells. What controls the range and efficiency of tension propagation (Aim 1)? The cell has many processes that can locally initiate changes in membrane tension (protrusions, contractions) and many cellular processes that are regulated by tension changes. Are there important functional differences for how these cellular programs transmit or receive membrane tension changes that may be important for cell polarity (Aim 2)? Migrating cells often need to coordinate their movement with other cells in order to achieve collective or cooperative motion. What is the impact of the membrane tension-polarity program in multicellular contexts such as encountered during collective or cooperative cell migration (Aim 3)? I will answer these questions by using a combination of optogenetics, force measurements, and advanced microscopy, and mathematical modeling. My research will elucidate the interplay between membrane mechanics and polarity during cell migration and will provide the foundation for my independent scientific niche of studying membrane mechanics during transendothelial migration. Towards this goal, I am supplementing the input of my postdoc supervisor, Dr Weiner (expert on cell polarity during migration) with a group of internationally recognized leaders at the interface of cell biology and biophysics: Carlos Bustamante (optical traps), Herve Turlier (mechanical modelling), Janis Burkhardt (cell migration). Japp van Buul and Ronen Alon, both experts on transendothelial migration. These scientists will act as both advisors and collaborators, helping me establish my own scientific niche in understanding the role of membrane mechanics in regulating transendothelial migration. I have worked with my mentor and network of collaborators and advisors to develop my research plan and construct a tailored career development program to help launch my independent career as a tenure-track principal investigator.