Abstract
One goal of cell biology is to understand how cells adopt different shapes in response to varying environmental and cellular conditions. Achieving a comprehensive understanding of the relationship between cell shape and environment requires a systems-level understanding of the signalling networks that respond to external cues and regulate the cytoskeleton. Classical biochemical and genetic approaches have identified thousands of individual components that contribute to cell shape, but it remains difficult to predict how cell shape is generated by the activity of these components using bottom-up approaches because of the complex nature of their interactions in space and time. Here, we describe the regulation of cellular shape by signalling systems using a top-down approach. We first exploit the shape diversity generated by systematic RNAi screening and comprehensively define the shape space a migratory cell explores. We suggest a simple Boolean model involving the activation of Rac and Rho GTPases in two compartments to explain the basis for all cell shapes in the dataset. Critically, we also generate a probabilistic graphical model to show how cells explore this space in a deterministic, rather than a stochastic, fashion. We validate the predictions made by our model using live-cell imaging. Our work explains how cross-talk between Rho and Rac can generate different cell shapes, and thus morphological heterogeneity, in genetically identical populations.
Highlights
Cell shape results from dynamic interactions between the cytoskeleton, cell membrane and adhesion complexes that interface with the extracellular environment, often via the actions of regulatory signal transduction systems [1,2,3,4]
A state space defined by seven different shapes
To quantify the number of cell shapes that can be adopted by a motile metazoan cell, we made use of a dataset where we previously quantified the cell shape of both wild-type Drosophila BG-2 cells, and BG-2 cells after systematic RNAi and/or gene overexpression of different cytoskeletal components and regulators, including Rho-family GTPases, Rho GTP exchange factors (RhoGEFs) and Rho GTPase activating proteins (RhoGAPs) [26]—termed treatment conditions (TCs) [26]
Summary
Cell shape results from dynamic interactions between the cytoskeleton, cell membrane and adhesion complexes that interface with the extracellular environment, often via the actions of regulatory signal transduction systems [1,2,3,4]. Specific shapes are essential for particular cellular behaviours such as migration. In many cells, motility is generated by formation of filopodial and lamellipodial protrusions at the leading edge (LE), which become sites of extensive adhesion to the underlying substrate generating traction, while at the trailing edge (TE), high contractility and the disassembly of adhesions generate a propulsive force [5]. Efficient migration requires that a cell ‘finds’ the appropriate set of migratory shapes from a space of all the shapes it could possibly assume [6]. Deterministic or stochastic searches of shape space are likely to underpin the morphological heterogeneity of different genetically identical populations [7].
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