Balance between cell−substrate adhesion and myosin contraction determines the frequency of motility initiation in fish keratocytes

Significance Symmetry breaking and motility initiation are required for many physiological and pathological processes, but the mechanical mechanisms that drive symmetry breaking are not well understood. Fish keratocytes break symmetry spontaneously, in the absence of external cues, with myosin-driven actin flow preceding rear retraction. Here we combine experimental manipulations and mathematical modeling to show that the critical event for symmetry breaking is a flow-dependent, nonlinear switch in adhesion strength. Moreover, our results suggest that mechanical feedback among actin network flow, myosin, and adhesion is sufficient to amplify stochastic fluctuations in actin flow and trigger symmetry breaking. Our mechanical model for symmetry breaking in the relatively simple keratocyte provides a framework for understanding motility initiation in more complex cell types. Cells are dynamic systems capable of spontaneously switching among stable states. One striking example of this is spontaneous symmetry breaking and motility initiation in fish epithelial keratocytes. Although the biochemical and mechanical mechanisms that control steady-state migration in these cells have been well characterized, the mechanisms underlying symmetry breaking are less well understood. In this work, we have combined experimental manipulations of cell−substrate adhesion strength and myosin activity, traction force measurements, and mathematical modeling to develop a comprehensive mechanical model for symmetry breaking and motility initiation in fish epithelial keratocytes. Our results suggest that stochastic fluctuations in adhesion strength and myosin localization drive actin network flow rates in the prospective cell rear above a critical threshold. Above this threshold, high actin flow rates induce a nonlinear switch in adhesion strength, locally switching adhesions from gripping to slipping and further accelerating actin flow in the prospective cell rear, resulting in rear retraction and motility initiation. We further show, both experimentally and with model simulations, that the global levels of adhesion strength and myosin activity control the stability of the stationary state: The frequency of symmetry breaking decreases with increasing adhesion strength and increases with increasing myosin contraction. Thus, the relative strengths of two opposing mechanical forces—contractility and cell−substrate adhesion—determine the likelihood of spontaneous symmetry breaking and motility initiation.