(Link-Sign-Mech-Furr) Linking Signalling to Mechanics and Shape Changes in Mitotic Furrowing

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During mitosis, cells undergo complex shape changes, where they round up, elongate and assemble a division furrow. Shape changes arise in response to spatiotemporal gradients in cortical tension controlled by an intricate signalling network. Patterning of cortical tension is controlled by the activity of RhoGTPases, which are key regulators of the cytoskeleton and contractility. They are regulated by a diverse set of RhoGEFs/RhoGAPs, and spatiotemporal recruitment of these to the membrane patterns the tension gradients. We do not know why multiple RhoGEFs and RhoGAPs overlap spatially and temporally to control furrow formation and ingression. While we know that furrow ingression necessitates an increase in myosin contractility and a reorganisation of the cortex, we do not know how each RhoGEF/GAP contributes to these events. My overall goal is to determine how spatiotemporal recruitment of RhoGEFs/GAPs controls cell mechanics to drive shape change during furrowing. First, the molecular, structural and mechanical changes during furrowing will be characterised. Molecular and mechanical changes induced by each RhoGEF/GAP participating in furrowing will be investigated. Then, the interplay of RhoGEFs/ GAPs will be examined.I will use a combination of optical live and super-resolution microscopy and Atomic force microscopy to investigate structural and mechanical changes. To determine the role of each RhoGEF/GAP, I will design optogenetic actuators that enable spatiotemporal control of signalling. By combining two actuators, I will investigate the interplay between RhoGEFs/GAPs. I will use the results as input parameters for computational modelling of cell shape change based on the spatiotemporal localisation of signalling.