Chugh, P; (2016) Organisation of the actomyosin cortex during the cell cycle. Doctoral thesis , UCL (University College London).

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Abstract

Cell shape control is key to a number of fundamental biological processes, including cell division and migration. Improper cell shape regulation has been associated with diseases like cancer. Animal cell shape is controlled primarily by the cortex, a thin actomyosin network underlying the plasma membrane. The architecture and dynamics of the cortical network determine global physical properties of the cell surface, such as surface tension. Previous studies have shown that cortex tension increase drives cell rounding in mitosis. However, the changes in cortex network organisation that dictate changes in tension remain largely unexplored. In my PhD, I investigated cortex thickness, a fundamental property of the cortex that impacts cortex mechanics. Using a sub-resolution image analysis method developed in the lab for cortex thickness measurement, I found that the cortex undergoes thinning at mitosis entry. I then explored the mechanisms of thickness regulation using a targeted-screen approach and discovered that knock down of proteins that regulate actin assembly/disassembly and thus filament length, resulted in altered cortex thickness and cortical tension. Agent-based simulations of the cortex revealed a non-monotonic relationship between actin filament length, cortex thickness and tension that accounts for my experimental observations. I further explored the architecture of the cortex, focusing on cortex surface density, transversal actin density and the localisation of actin binding proteins. I could show that the cortex density (at the surface and in the transversal direction) increases significantly from interphase to mitosis. Interestingly, I found that the cortical distribution of myosin-2 motors, which generate tension, is sterically restricted due to their large size. I could show that myosins penetrate deeper into the interphase cortex compared to mitosis. This steric effect could strongly influence the generation of cortical tension. My findings on how cortex thickness, density and cortical protein localisation control tension bring new insights into how microscopic properties of the cortex regulate the mesoscopic properties of cells, which in turn drive cellular morphogenesis.

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