Title: Actin cortex mechanics and the morphogenesis of animal cells
Funder: Medical Research Council

Abstract: The shape of animal cells is primarily determined by the cellular cortex, a cross-linked network of actin and myosin underlying the plasma membrane. The cortex enables the cell to resist and exert forces. As such, it plays a central role during events involving cell deformation, such as division and locomotion, and in the patho-physiology of diseases such as cancer, in which cortical mechanics are often misregulated. Despite its importance, very little is known about cortex composition, regulation, and mechanics. To address these questions, we combine cell and molecular biology experiments, quantitative imaging and theoretical modelling. This interdisciplinary approach allows us to investigate the basic mechanisms of morphogenesis across scales, from molecular players to emerging physical behaviours. The group follows three main research directions. We investigate cell shape control during cell division. Cell cleavage during cytokinesis relies on a controlled reorganisation of the cortex, which concentrates at the equator where it drives furrow ingression. We have recently shown that even though strong cortical forces are generated at the equator, the cortex remaining at the poles of the cell makes cytokinesis inherently unstable; an imbalance in cortex contractility between the two poles can compromise the accurate positioning of the constriction ring and result in contractile oscillations. A theoretical model based on a competition between cortex turnover and contraction dynamics accurately accounts for the oscillations. Taken together, our findings reveal an inherent instability in the shape of the dividing cell, indicating that polar cortex contractility must be tightly controlled during cytokinesis. When this control fails, the cortex displays oscillatory instabilities. We are now exploring how cell mechanics are regulated during cell division in order to ensure stable and symmetric cleavage. Furthermore, we started investigating whether contractile oscillations displayed by the apical cortex during epithelial tissue morphogenesis are driven by a similar mechanism. We also study cell shape mechanics during migration, with a particular focus on the formation and function of blebs, cellular protrusions driven by cortex contractions. Blebs are a common alternative to lamellipodia during migration in 3-dimensional environments. We are investigating the specific contributions of blebs and lamellipodia to cell motility in culture cells and in vivo, during zebrafish gastrulation. Furthermore, we are exploring the physical mechanisms of cell translocation during bleb-based migration, which seems to occur without specific adhesions to the substrate. To this aim, we use microfluidics channels, which present a well-defined geometry, allowing for quantitative measurements of cell shape and cortex dynamics during migration. Finally, we are investigating how cortical physical properties are controlled at the network level. As the cortex is less than 300 nm thick, close to the resolution limit of a standard optical microscope, the spatial organisation of cortical components has been elusive. We have developed methods to probe cortex organisation using sub-resolution image analysis. We are investigating the thickness of the cortex and the localisation of essential components, such as myosin motors. Our long-term aim is to understand how cortical contractility is controlled at the molecular level, in healthy and pathological conditions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE