Robo2 drives target selective peripheral nerve regeneration in response to glia derived signals

Peripheral nerves are divided into multiple branches leading to divergent synaptic targets. This poses a remarkable challenge for regenerating axons as they select their original trajectory at nerve branch-points. Despite implications for functional regeneration, the molecular mechanisms underlying target selectivity are not well characterized. Zebrafish motor nerves are composed of a ventral and a dorsal branch that diverge at a choice point, and we have previously shown that regenerating axons faithfully select their original branch and targets. Here we identify Robo2 as a key regulator of target selective regeneration. We demonstrate that Robo2 function in regenerating axons is required and sufficient to drive target selective regeneration, and that Robo2 acts in response to glia located precisely where regenerating axons select the branch-specific trajectory to prevent and correct axonal errors. Combined our results reveal a glia derived mechanism that acts locally via axonal Robo2 to promote target selective regeneration.