Corrections in single-cell migration path in vivo are controlled by pulses in polar Rac1 activation

Directed migration of single cells is central to a large number of processes in development and adult life. Corrections to the migration path of cells are often characterized by periodic loss of polarity that is followed by the generation of a new leading edge in response to guidance cues, a behavior termed "run and tumble." While this phenomenon is essential for accurate arrival at migration targets, the precise molecular mechanisms responsible for the periodic changes in cell polarity are unknown. To investigate this issue, we employ germ cells in live zebrafish embryos as an in vivo model and show that a tunable molecular network controls periodic pulsations of Rac1 activity and actin polymerization. This process, which we term "polar pulsations," is responsible for the transitions between the run and tumble phases. In addition, we provide evidence for the role of apolar blebbing activity during tumble phases in erasing the memory of the previous front-back polarity of the migrating cell. To understand how the molecular components give rise to this distinct behavior, we develop a minimal mathematical model of the biochemical network that accounts for the observed cell behavior. Together, our in vivo findings and the mathematical model suggest that a pulsatory signaling network regulates the accuracy of individual cell migration.