CRUK-UCL and Cancer Domain Multidisciplinary Seminar Series

Complex shape or tissue changes during morphogenesis require the presence of gradients of tension arising from local differences in cytoskeletal activity. Understanding how such patterned internal stress lead to deformations of the cell surface is challenging. Here we will introduce a physical description of active surfaces that allows to make this connection. Cell or tissue morphogenesis indeed often involve the deformation of two-dimensional surfaces that are driven out of equilibrium by inherently active biological processes. For instance, epithelia deform during development as a result of cellular processes such as cell growth or cytoskeletal force generation, or the cell surface deforms during cell division as a result of patterned forces generated in the actin cortex.  Here we will discuss deformations of a spherical active surface that is subjected to patterned active internal stresses and torques.

A limitation of such approaches is to understand how active force generation is controlled by signalling within the cell. Actin filaments within the cortex are mainly generated by two nucleators, Arp2/3 that generates branched actin networks and the formin mDia1 that forms linear arrays of filaments. A general challenge in cytoskeletal research is to understand how nucleators interplay. Nucleation promoting factors (NPFs), which activate or maintain nucleator activity downstream of RhoGTPases, may coordinate nucleator activity. Using proteomics and single molecular approaches, we identify an NPF which controls the interplay between mDia1 and Arp2/3. This allows cells to control the length and branching of filaments, two key parameters that influence the mechanics of polymer gels.

Upstream from actin nucleators and NPFs, heterogeneities in mechanics arise from local activation of signalling at the cortex. For example, in anaphase, accumulation of F-actin and myosin at the midzone arises from the combined action of MgcRacGAP, MP-GAP, Ect2, and GEF-H1. Concomitantly, at the poles, accumulation of Ran-GTP leads to anillin clearing and accumulation of PP1R7/sds22 leads to loss of myosin and F-actin and subsequently softening of the cortex. To understand the link between signalling and mechanics, we trigger localisation of RhoGEFs/GAPs to the cortex using optogenetics and monitor changes in cell mechanics using AFM.

We will discuss our preliminary data on the control of mechanics by signalling and how to predict shape change from the localisation of signalling proteins.

• Prof Guillaume Charras Academic Profile
• Dr Guillaume Salbreux - Theoretical Physics of Biology Lab