Actin and actin-associated proteins migrate within various cell types. To uncover the mechanism of their migration, we analyzed actin waves, which translocate actin and actin-associated proteins along neuronal axons toward the growth cones. We found that arrays of actin filaments constituting waves undergo directional assembly and disassembly, with their polymerizing ends oriented toward the axonal tip, and that the lateral side of the filaments is mechanically anchored to the adhesive substrate. A combination of live-cell imaging, molecular manipulation, force measurement, and mathematical modeling revealed that wave migration is driven by directional assembly and disassembly of actin filaments and their anchorage to the substrate. Actin-associated proteins co-migrate with actin filaments by interacting with them. Furthermore, blocking this migration, by creating an adhesion-free gap along the axon, disrupts axonal protrusion. Our findings identify a molecular mechanism that translocates actin and associated proteins toward the cell's leading edge, thereby promoting directional cell motility.

Actin filaments and associated proteins undergo wave-like movement in various cell types. Recent studies with cutting-edge analyses, including live-cell imaging, biophysical monitoring and manipulation, and mathematical modeling, have highlighted roles of 'actin waves' in cellular protrusion, polarization, and migration. The prevailing models to explain the wave-like dynamics of actin filaments involve an activator-inhibitor mechanism. In addition, axonal actin waves migrate by means of directional assembly and disassembly of membrane-anchored actin filaments, and thus represent a new type of machinery that translocates their component molecules to the cell edge. Here, we review recent advances in our understanding of the generation, mobility, and functions of actin waves, and discuss how actin waves may self-organize into the molecular machinery underlying cell morphogenesis.

SignificanceCell migration directed by substrate-bound chemical cues is called haptotaxis. This study shows that grip and slip between the cell adhesion molecule (CAM) L1-CAM and the adhesive substrates, which occur asymmetrically under the growth cone, direct growth cone migration mediated by laminin. This mechanism is disrupted in a human patient of L1-CAM syndrome, suffering corpus callosum agenesis and corticospinal tract hypoplasia. These findings provide a conceptual framework for understanding the regulation and dysregulation of cell migration on the bases of force generation.