Actin Retrograde Flows Stabilize Cell Polarity by Mechano-Chemical Feedback Loops in Migrating Cells

Abstract

Cell migration has important functions in immune response, development and cancer proliferation. Cell movement essentially requires the establishment of an axis of polarity. To maintain migration in one direction - called persistent cell migration - the polarity axis needs to be stabilized in the direction of movement.Biochemical feedback loops between signaling molecules have been recognized to play an important role for stabilizing cell polarity by reinforcing actin polymerization at the leading edge. Here we describe a reverse feedback mechanism coupling the retrograde flowing actin cytoskeleton in migrating cells back to cell polarity and persistent migration supporting an essential mechano-chemical coupling of signaling cascades and the flowing cytoskeletal meshwork in migrating cells (Maiuri et al., 2015). We used genetic, physical and chemical tools to modulate cytoskeletal flows in migrating dendritic cells and found a strong increase in the stability of cellular polarization and migration persistence upon increasing retrograde flow speed. We provide experimental evidence that the spatial distribution of different actin binding proteins (Myosin-GFP, Lifeact-GFP and Utrophin-GFP) with varying actin-binding strength gets significantly shifted towards the cell rear for increasing retrograde flow speeds upon sufficient coupling to the flowing actin network. Finally we show that a minimal theoretical model build on the mechano-chemical coupling between polarity markers and cytoskeletal flows can predict the stability of cell polarity in dependence on retrograde flow speeds and can capture the broad range of cell migration phenotypes from Brownian, to persistent and intermittent random walks.Maiuri, P.∗, Rupprecht, J.-F.∗, Wieser, S.∗, Ruprecht, V., Benichou, O., Carpi, N., Coppey, M., De Beco, S., Gov, N., Heisenberg, C.-P., et al. (2015). Actin Flows Mediate a Universal Coupling between Cell Speed and Cell Persistence. Cell 161, 374-386. ∗contributed equally.