Steering cell migration by alternating blebs and actin-rich protrusions.

Abstract

BACKGROUND: High directional persistence is often assumed to enhance the efficiency of chemotactic migration. Yet, cells in vivo usually display meandering trajectories with relatively low directional persistence, and the control and function of directional persistence during cell migration in three-dimensional environments are poorly understood. RESULTS: Here, we use mesendoderm progenitors migrating during zebrafish gastrulation as a model system to investigate the control of directional persistence during migration in vivo. We show that progenitor cells alternate persistent run phases with tumble phases that result in cell reorientation. Runs are characterized by the formation of directed actin-rich protrusions and tumbles by enhanced blebbing. Increasing the proportion of actin-rich protrusions or blebs leads to longer or shorter run phases, respectively. Importantly, both reducing and increasing run phases result in larger spatial dispersion of the cells, indicative of reduced migration precision. A physical model quantitatively recapitulating the migratory behavior of mesendoderm progenitors indicates that the ratio of tumbling to run times, and thus the specific degree of directional persistence of migration, are critical for optimizing migration precision. CONCLUSIONS: Together, our experiments and model provide mechanistic insight into the control of migration directionality for cells moving in three-dimensional environments that combine different protrusion types, whereby the proportion of blebs to actin-rich protrusions determines the directional persistence and precision of movement by regulating the ratio of tumbling to run times.This work was supported by the Max Planck Society, the Medical Research Council UK (core funding to the MRC LMCB), and by grants from the Polish Ministry of Science and Higher Education (454/N-MPG/2009/0) to EKP, the Deutsche Forschungsgemeinschaft (HE 3231/6-1 and PA 1590/1-1) to CPH and EKP, a A*Star JCO career development award (12302FG010) to WY and a Damon Runyon fellowship award to ADM (DRG 2157-12). This work was also supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001317), the UK Medical Research Council (FC001317), and the Wellcome Trust (FC001317) to G