Modeling cell shape diversity arising from complex Rho GTPase dynamics

ABSTRACT It is well known that cells exhibit a variety of morphologically distinct responses to their environments that manifest in their cell shape. Some protrude uniformly to increase substrate contacts, others are broadly contrac-tile, some polarize to facilitate migration, and yet others exhibit mixtures of these responses. Prior imaging studies have identified a discrete collection of shapes that the majority of cells display and have demonstrated links between those shapes and activity levels of the cytoskeletal regulators Rho GTPases. Here we use a novel computational modeling approach to demonstrate that well known Rho GTPase signaling dynamics naturally give rise to this diverse but discrete (rather than continuum) set of morphologies. Specifically, the combination of auto-activation and mutually-antagonistic crosstalk between GTPases along with the conservative membrane (un)binding dynamics readily explain at least 6 of the 7 commonly observed morphologies. We further use this methodology to map the entire parameter space of this model and show that in appropriate regimes, individual parameter sets give rise to a variety of different morphologies. This provides an explanation for how seemingly similar cells of the same fate derived from the same population can exhibit a diverse array of cell shapes in imaging studies. These results thus demonstrate that Rho GTPases form the core of a cytoskeletal regulatory system governing cell shape, further supporting the picture that they act as a central signaling hub determining how cells respond to their environmental context.