Repellent and Attractant Guidance Cues Initiate Cell Migration by Distinct Rear-Driven and Front-Driven Cytoskeletal Mechanisms

Attractive and repulsive cell guidance is essential for animal life and important in disease. Cell migration toward attractants dominates studies [1-8], but migration away from repellents is important in biology yet relatively little studied [5, 9, 10]. It is widely held that cells initiate migration by protrusion of their front [11-15], yet this has not been explicitly tested for cell guidance because cell margin displacement at opposite ends of the cell has not been distinguished for any cue. We argue that protrusion of the front, retraction of the rear, or both together could in principle break cell symmetry and start migration in response to guidance cues [16]. Here, we find in the Dictyostelium model [6] that an attractant-cAMP-breaks symmetry by causing protrusion of the front of the cell, whereas its repellent analog-8CPT-breaks symmetry by causing retraction of the rear. Protrusion of the front of these cells in response to cAMP starts with local actin filament assembly, while the delayed retraction of the rear is independent of both myosin II polarization and of motor-based contractility. On the contrary, myosin II accumulates locally in the rear of the cell in response to 8CPT, anticipating retraction and required for it, while local actin assembly is delayed and couples to delayed protrusion at the front. These data reveal an important new concept in the understanding of cell guidance.