How the cells break symmetry and organize their edge activity to move directionally is a fundamental question in cell biology. Physical models of cell motility commonly rely on gradients of regulatory factors and/or feedback from the motion itself to describe polarization of edge activity. Theses approaches, however, fail to explain cell behavior prior to the onset of polarization. Our analysis using the model system of polarizing and moving fish epidermal keratocytes suggests a novel and simple principle of self-organization of cell activity in which local cell-edge dynamics depends on the distance from the cell center, but not on the orientation with respect to the front-back axis. We validate this principle with a stochastic model that faithfully reproduces a range of cell-migration behaviors. Our findings indicate that spontaneous polarization, persistent motion, and cell shape are emergent properties of the local cell-edge dynamics controlled by the distance from the cell center.The ability to break symmetry and move directionally is an essential property of most eukaryotic cells [1][2][3]. This happens in response to external stimuli, but also spontaneously [4][5][6]. Persistent motion requires segregation of cell-edge activities, so that protrusion happens predominantly at the front, and retraction at the back of the cell. In contrast, in cells exploring their environment, edge activity is on average spatially isotropic, but fluctuates in time between protrusion and retraction [7][8][9][10][11]. Thus both exploratory activity and the directional motion depend on the transitions between protrusion and retraction but how the cell chooses between these two regimes to establish spatial and temporal patterns of edge activity remains unclear. It is believed that in migrating cells a directional mechanism at the scale of the whole cell, e.g. a global gradient of cytoskeletal and/or signaling components, orchestrates cell-edge dynamics according to the overall motion direction [1,5,[12][13][14] This concept is limited in that external directional stimuli [5,13] in combination with internal diffusible signals interacting through feedback loops [15][16][17][18][19][20], feedback from the motion itself [6,[21][22][23][24], or very large and highly correlated perturbation to induce the polarized states [25] have to be invoked in order to establish the polarity axis. Fish epidermal keratocytes, thanks to their robust polarity, simple shape, and persistent motion, are a classic model system to study polarization and directional migration [3,26]. Analysis of the edge dynamics of these cells led to the concept of Graded Radial Extension (GRE), which links local edge dynamics to the resulting overall cell motion: protrusion and retraction are * Now at SICHH, Swiss Integrative Center for Human Health, Fribourg, Switzerland directed normally to the cell edge with rates that are graded depending on the orientation with respect to the motion direction [26]. This model inspired several studies searching for the underlying mech...

Plasma membrane tension and the pressure generated by actin polymerization are two antagonistic forces believed to define the protrusion rate at the leading edge of migrating cells [1-5]. Quantitatively, resistance to actin protrusion is a product of membrane tension and mean local curvature (Laplace's law); thus, it depends on the local geometry of the membrane interface. However, the role of the geometry of the leading edge in protrusion control has not been yet investigated. Here, we manipulate both the cell shape and substrate topography in the model system of persistently migrating fish epidermal keratocytes. We find that the protrusion rate does not correlate with membrane tension, but, instead, strongly correlates with cell roundness, and that the leading edge of the cell exhibits pinning on substrate ridges-a phenomenon characteristic of spreading of liquid drops. These results indicate that the leading edge could be considered a triple interface between the substrate, membrane, and extracellular medium and that the contact angle between the membrane and the substrate determines the load on actin polymerization and, therefore, the protrusion rate. Our findings thus illuminate a novel relationship between the 3D shape of the cell and its dynamics, which may have implications for cell migration in 3D environments.

Platelets are produced by bone marrow megakaryocytes through cytoplasmic protrusions, named native proplatelets (nPPT), into blood vessels. Proplatelets also refer to protrusions observed in megakaryocyte culture (cPPT) that are morphologically different. Contrary to cPPT, the mechanisms of nPPT formation are poorly understood. We show here in living mice that nPPT elongation is in equilibrium between protrusive and retraction forces mediated by myosin-IIA. We also found, using WT and β1-tubulin-deficient mice, that microtubule behavior differs between cPPT and nPPT, being absolutely required in vitro, while less critical in vivo. Remarkably, microtubule depolymerization in myosin-deficient mice did not affect nPPT elongation. We then calculated that blood Stokes'forces may be sufficient to promote nPPT extension, independently of myosin and microtubules. Together, we propose a new mechanism for nPPT extension that might explain contradictions between severely affected cPPT production and moderate platelet count defects in some patients and animal models.

Highlights d Traction forces correlate with the distance from the center to the edge of the cell d Analysis of edge and stress dynamics suggests that stress triggers edge retraction d Unlike traction stress, actin flow correlates with distance only during retraction d Simple model reproduces force-distance relationship