Cell polarity and mechanotransduction

Little is known about how neutrophils and other cells establish a single zone of actin assembly during migration. A widespread assumption is that the leading edge prevents formation of additional fronts by generating long-range diffusible inhibitors or by sequestering essential polarity components. A significant challenge in discriminating between the many classes of models for cell polarity is that many of the underlying positive and negative feedback components have not been identified, and even for the known components, the key biophysical parameters are unknown. We performed experiments that discriminate between models of long-range inhibition without requiring detailed knowledge of the underlying molecular components. We used morphological perturbations, cell-severing experiments, and computational simulations to show that diffusion-based mechanisms are not sufficient for long-range inhibition by the pseudopod. Instead, we show that plasma membrane tension is the dominant source of inhibition. We find that membrane tension doubles during leading-edge protrusion, and increasing tension is sufficient for long-range inhibition of leading edge signals. Furthermore, reducing membrane tension causes uniform actin assembly and a loss of polarity for leading edge signals. Our experiments suggest that tension, rather than diffusible molecules generated or sequestered at the leading edge, is the dominant long-range inhibitor that constrains the spread of the existing front and prevents the formation of secondary fronts. These interdisciplinary experiments shed new light on the fundamental question of how cells establish a single axis of polarity. Houk et al., Cell, 148: 175-188 (2012); Diz-Munoz et al., 2013. More broadly, physical forces are emerging as an organizing principle for many global cell behaviors.  Mechanical forces and feedbacks likely enable the rapid dynamics of individual molecules to be integrated into the large-scale organization of migrating cells.   We have recently identified the mechanosensory pathway that links changes in tension to changes in actin organization (Diz-Munoz et al, 2016).  We are continuing to probe the role of force as a signal integrator in cell signaling and polarity (Tamas Nagy).