How cytoskeletal forces trigger nucleus activation during confined cell motility – SQUEEZACTIV

With the huge progress in molecular biology and biochemistry, the study of cell function was possible with stripped-down systems and using soft matter concepts. The dynamic assembly of the visco-elastic cytoskeleton generates forces and movement of cells, a function called "cell motility". Fundamental descriptions of cell motility, based on membrane deformations by the cytoskeleton, are now available. Yet none of these models include the contribution of the nucleus, the stiffest cell organelle. Because cells in the body have to squeeze through narrow spaces that are smaller than nucleus size, and that muscle cell nuclei move and deform during cell maturation through the action of the cytoskeleton, time is now ripe to address how the nucleus contributes to cell motility and how it is actively deformed by the cytoskeleton. We will use soft matter approaches combined with the determination of cell activity through a Langevin equation analysis. Moreover, nuclear squeezing produced during confined cell motility is expected to mechanically activate the nucleus content, a mechanism called “mechano-transduction” that may affect chromatin distribution. We will decipher the activation process of the nucleus in motile cells by comparing active and passive squeezing of cells with microfluidic tools. We will extract, from nuclear shape, protein and chromatin distributions, their deterministic and stochastic contributions to the movement. Using biochemical tools, we will alter the activity of cell motility and measure quantitatively how these contributions differ. Ultimately, we will provide a physical framework to "measure" how and of how much the nucleus is activated, an approach that will pave the way to controlling cell fates involving nucleus movement and deformation.