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The inherent morphological potential of the actin cortex and the mechanics of shape control during cell division

Final Report Summary - MORPHOCORDIV (The inherent morphological potential of the actin cortex and the mechanics of shape control during cell division)

The shape of animal cells is primarily determined by the cellular cortex, a cross-linked network of actin and myosin lying directly beneath the plasma membrane. Although it is increasingly clear that the study of cell mechanics is essential to understand cellular morphogenesis, the physical properties of the cortex are poorly understood. Our previous study of the mechanics of cytokinesis identified cortex tension, cortex turnover and cellular elasticity as key mechanical parameters controlling cell morphology. Perturbing the mechanical balance of these three parameters in dividing cells leads to shape instabilitites driven by contractile oscillations of the cell poles, resulting in destabilization of the equatorial ring and division failure. Our working hypothesis is that modulating these key parameters of cellular mechanics can lead to a variety of cell morphogenetic behaviors, including symmetric ingression of a contractile ring, cortex oscillations, and asymmetric divisions.

The overarching question of the MorphoCorDiv project was the investigation of the inherent mechanical potential of the actomyosin cortex for cell shape changes, specifically focusing on cell division. The key aims were to unveil how cortex mechanical properties are regulated, and how cortex mechanics determines cell shape during cell division.

We investigated how key physical properties of the cortex are controlled at the molecular level. We showed that different actin regulators contribute differentially to actin dynamics and turnover (Bovellan et al, Curr Biol 2014). Using a combination of cell biology experiments, sub-resolution microscopy, physical measurements and computational modeling, we then revealed that the nanoscale organisation of actin filaments in the cortex is an essential regulator of cell surface mechanics (Chugh et al, Nat Cell Biol 2017). Furthermore, using super-resolution imaging of myosins in the actin cortex, we could show that myosin orientation and penetration within the cortical network changes during the cell cycle, strongly affecting cortical tension. Together, these findings identify several novel mechanisms of cell surface tension regulation, which was so far believed to be predominantly controlled by myosin motor amount and activity. Finally, we showed that the plasma membrane can modulate the mechanics of cell contractions, as the dynamics of membrane folding and flows can interfere with cortex contractions.

In parallel, we have been investigating cell division mechanics and cell size heterogeneities in mouse embryonic stem cells. We are currently exploring how size and division asymmetries affect cell fate decisions in these cells.

Finally, we have been using isolated cellular blebs as a model to investigate cortex architecture. Blebs are membrane protrusions containing a prominent cortex; blebs can be isolated, and their size makes them amenable to cryo-electron tomography. In collaboration with the group of Ohad Medalia, we have characterized the organization of actin filaments at the cortex of isolated blebs by cryo-electron tomography. This unveiled the 3-dimensional architecture of the cortex at unprecedented resolution.

Taken together, the MorphoCorDiv project highlights that the nanoscale architecture of the cortex is central to the regulation of cortical tension, and as a result, cellular shape.