Curated Optogenetic Publication Database

Abstract: During development, wound healing and cancer invasion, migrating cell clusters feature highly protrusive leader cells at their front. Leader cells are thought to pull and direct their cohort of followers, but whether their local action is enough to guide the entire cluster, or if a global mechanical organization is needed, remains controversial. Here we show that the effectiveness of the leader–follower organization is proportional to the asymmetry of traction and tension within cell clusters. By combining hydrogel micropatterning and optogenetic activation, we generate highly protrusive leaders at the edge of minimal cell clusters. We find that the induced leader can robustly drag one follower but not larger groups. By measuring traction forces and tension propagation in clusters of increasing size, we establish a quantitative relationship between group velocity and the asymmetry of the traction and tension profiles. Modelling motile clusters as active polar fluids, we explain this force–velocity relationship in terms of asymmetries in the active traction profile. Our results challenge the notion of autonomous leader cells, showing that collective cell migration requires global mechanical organization within the cluster.

Abstract: Secretory trafficking from the endoplasmic reticulum (ER) is subject to regulation by extrinsic and intrinsic factors. While much of the focus has been on biochemical triggers, little is known whether and how the ER is subject to regulation by mechanical signals. Here, we show that COPII-dependent ER-export is regulated by mechanical strain. Mechanotransduction to the ER was mediated via a previously unappreciated ER-localized pool of the small GTPase Rac1. Mechanistically, we show that Rac1 interacts with the small GTPase Sar1 to drive budding of COPII carriers and stimulate ER-to-Golgi transport. Altogether, we establish an unprecedented link between mechanical strain and export from the ER.

Abstract: Mechanical force controls fundamental cellular processes in health and disease, and increasing evidence shows that the nucleus both experiences and senses applied forces. Here we show that nuclear forces differentially control both passive and facilitated nucleocytoplasmic transport, setting the rules for the mechanosensitivity of shuttling proteins. We demonstrate that nuclear force increases permeability across nuclear pore complexes, with a dependence on molecular weight that is stronger for passive than facilitated diffusion. Due to this differential effect, force leads to the translocation into or out of the nucleus of cargoes within a given range of molecular weight and affinity for nuclear transport receptors. Further, we show that the mechanosensitivity of several transcriptional regulators can be both explained by this mechanism, and engineered exogenously by introducing appropriate nuclear localization signals. Our work sets a novel framework to understand mechanically induced signalling, with potential general applicability across signalling pathways and pathophysiological scenarios.

Abstract: It has long been proposed that the cell cycle is regulated by physical forces at the cell-cell and cell-extracellular matrix (ECM) interfaces1-12. However, the evolution of these forces during the cycle has never been measured in a tissue, and whether this evolution affects cell cycle progression is unknown. Here, we quantified cell-cell tension and cell-ECM traction throughout the complete cycle of a large cell population in a growing epithelium. These measurements unveil temporal mechanical patterns that span the entire cell cycle and regulate its duration, the G1-S transition and mitotic rounding. Cells subjected to higher intercellular tension exhibit a higher probability to transition from G1 to S, as well as shorter G1 and S-G2-M phases. Moreover, we show that tension and mechanical energy are better predictors of the duration of G1 than measured geometric properties. Tension increases during the cell cycle but decreases 3 hours before mitosis. Using optogenetic control of contractility, we show that this tension drop favours mitotic rounding. Our results establish that cell cycle progression is regulated cooperatively by forces between the dividing cell and its neighbours.