Seminars

Neutrophils migrate in large numbers to sites of infection, injury, and inflammation to defend the body against pathogens. To get there, they use chemotaxis to follow gradients of attractants, and these cells are highly tuned for directional sensing and persistent migration. Although, many of the key molecular components are known, the basic mechanisms mediating these two processes are still not resolved. To test models of directional sensing directly, and to determine how receptor inputs are integrated with pre-existing cell polarity, we combined a light-controllable receptor with biosensors for downstream signaling. Contrary to a long-standing model, we saw no evidence for a long-range negative signal downstream of receptors. Instead, receptor inputs are processed locally, and the cytoskeleton plays a central role in integrating signals for directional decisions. Local cytoskeletal structures control signal spread and create asymmetry in sensitivity to promote persistent migration with gradual turning. We are now developing and using new optogenetic tools to study feedback between the actin cytoskeleton and the Rho GTPases to determine how it promotes chemotaxis.