title: Balance between cell-substrate adhesion and myosin contraction determines the frequency of motility initiation in fish keratocytes.
abstract: 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.
authors.affiliation: Department of Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Erin
authors.initials: E
authors.lastname: Barnhart
authors.affiliation: Department of Neurobiology, Physiology and Behavior, University of California, Davis, CA 95616;
authors.forename: Kun-Chun
authors.initials: KC
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Greg M
authors.initials: GM
authors.lastname: Allen
authors.affiliation: Department of Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305; and mogilner@cims.nyu.edu theriot@stanford.edu.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Theriot
authors.affiliation: Courant Institute of Mathematical Sciences and Department of Biology, New York University, New York, NY 10012 mogilner@cims.nyu.edu theriot@stanford.edu.
authors.forename: Alex
authors.initials: A
authors.lastname: Mogilner
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D002448:Cell Adhesion; D002465:Cell Movement; D023681:Cichlids / Q000378:metabolism*; D003198:Computer Simulation; D004847:Epithelial Cells / Q000166:cytology*; D009218:Myosins / Q000378:metabolism*; D017711:Nonlinear Dynamics
chemical_list: D000199:Actins; D009218:Myosins
keywords: adhesion; cell migration; myosin; symmetry breaking
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