Mechanism of shape determination in motile cells

Abstract

The shape of motile cells is determined by many dynamic processes spanning several orders of magnitude in space and time, from local polymerization of actin monomers at subsecond timescales to global, cell-scale geometry that may persist for hours. Understanding the mechanism of shape determination in cells has proved to be extremely challenging due to the numerous components involved and the complexity of their interactions. Here we harness the natural phenotypic variability in a large population of motile epithelial keratocytes from fish (Hypsophrys nicaraguensis) to reveal mechanisms of shape determination. We find that the cells inhabit a low-dimensional, highly correlated spectrum of possible functional states. We further show that a model of actin network treadmilling in an inextensible membrane bag can quantitatively recapitulate this spectrum and predict both cell shape and speed. Our model provides a simple biochemical and biophysical basis for the observed morphology and behaviour of motile cells.Cell shape emerges from the interaction of many constituent elements-notably, the cytoskeleton, the cell membrane and cellsubstrate adhesions-that have been studied in great detail at the molecular level 1-3 ; however, the mechanism by which global morphology is generated and maintained at the cellular scale is not understood. Many studies have characterized the morphological effects of perturbing various cytoskeletal and other cellular components (for example, ref. 4); yet, there have been no comprehensive efforts to try to understand cell shape from first principles. Here we address this issue in the context of motile epithelial keratocytes derived from fish skin. Fish keratocytes are among the fastest moving animal cells, and their motility machinery is characterized by extremely rapid molecular dynamics and turnover [5][6][7][8] . At the same time, keratocytes are able to maintain nearly constant speed and direction during movement over many cell lengths. Their shapes, consisting of a bulbous cell body at the rear attached to a broad, thin lamellipodium at the front and sides, are simple, stereotyped and notoriously temporally persistent 9,10 . The molecular dynamism of these cells, combined with the persistence of their global shape and behaviour, make them an ideal model system for investigating the mechanisms of cell shape determination.The relative simplicity of keratocytes has inspired extensive experimental and theoretical investigations into this cell type 5-17 , considerably advancing the understanding of cell motility. A notable example is the graded radial extension (GRE) model 12 , which was an early attempt to link the mechanism of motility at the molecular level with overall cell geometry. The GRE model proposed that local cell extension (either protrusion or retraction) occurs perpendicular to the cell edge, and that the magnitude of this extension is graded from a maximum near the cell midline to a minimum towards the sides. Although this phenomenological model has been shown experimentally ...

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