The development and maintenance of tissues requires collective cell movement, during which neighboring cells coordinate the polarity of their migration machineries. Here, we ask how polarity signals are transmitted from one cell to another across symmetrical cadherin junctions, during collective migration. We demonstrate that collectively migrating endothelial cells have polarized VE-cadherin-rich membrane protrusions, “cadherin fingers”, which leading cells extend from their rear and follower cells engulf at their front, thereby generating opposite membrane curvatures and asymmetric recruitment of curvature sensing proteins. In follower cells, engulfment of cadherin fingers occurs along with the formation of a lamellipodia-like zone with low actomyosin contractility, and requires VE-cadherin/catenin complexes and Arp2/3-driven actin polymerization. Lateral accumulation of cadherin fingers in follower cells precedes turning, and increased actomyosin contractility can initiate cadherin finger extension as well as engulfment by a neighboring cell, to promote follower behavior. We propose that cadherin fingers serve as guidance cues that direct collective cell migration.
Cell migration is driven by local membrane protrusion through directed polymerization of F-actin at the front. However, F-actin next to the plasma membrane also tethers the membrane and thus resists outgoing protrusions. Here, we developed a fluorescent reporter to monitor changes in the density of membrane-proximal F-actin (MPA) during membrane protrusion and cell migration. Unlike the total F-actin concentration, which was high in the front of migrating cells, MPA density was low in the front and high in the back. Back-to-front MPA density gradients were controlled by higher cofilin-mediated turnover of F-actin in the front. Furthermore, nascent membrane protrusions selectively extended outward from areas where MPA density was reduced. Thus, locally low MPA density directs local membrane protrusions and stabilizes cell polarization during cell migration.
Migrating cells move across diverse assemblies of extracellular matrix (ECM) that can be separated by micron-scale gaps. For membranes to protrude and reattach across a gap, actin filaments, which are relatively weak as single filaments, must polymerize outward from adhesion sites to push membranes towards distant sites of new adhesion. Here, using micropatterned ECMs, we identify T-Plastin, one of the most ancient actin bundling proteins, as an actin stabilizer that promotes membrane protrusions and enables bridging of ECM gaps. We show that T-Plastin widens and lengthens protrusions and is specifically enriched in active protrusions where F-actin is devoid of non-muscle myosin II activity. Together, our study uncovers critical roles of the actin bundler T-Plastin to promote protrusions and migration when adhesion is spatially-gapped.
A major component of cell migration is F-actin polymerization driven membrane protrusion in the 15 front. However, F-actin proximal to the plasma membrane also has a scaffolding role to support and attach the membrane. Here we developed a fluorescent reporter to monitor changes in the density of membrane proximal Factin during membrane protrusion and cell migration. Strikingly, unlike total F-actin concentration, which is high in the front of migrating cells, the density of membrane proximal F-actin is low in the front and high in the back. Furthermore, local membrane protrusions only form following local decreases in membrane proximal F-actin 20 density. Our study suggests that low density of membrane proximal F-actin is a fundamental structural parameter that locally directs membrane protrusions and globally stabilizes cell polarization during cell migration.One Sentence Summary: Membrane protrusion and cell migration are directed by local decreases in the density of membrane proximal F-actin 25
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