Pre-existing pathways promote precise projection patterns

A large body of evidence shows that molecular cues promote specific synapse formation by guiding axons and by mediating their association with targets, but much less is known about the contribution of physical cues (such as mechanical constraints) to these processes. Here we used the peripheral motor system to investigate the latter issue. In living mice, we viewed individual motor axons bearing a fluorescent reporter, and mapped the cohort of muscle fibers that they innervated both before and after nerve damage. When gross trauma was minimized (by a nerve-crushing rather than nerve-cutting procedure), regenerating axons retraced their former pathways, bifurcated at original branch points, and formed neuromuscular junctions on the same fibers that they originally innervated. Axonal growth through tubes of non-neural cells seemed to account for this specificity, and specificity degraded when the tubes were cut. These results suggest that nonspecific guidance cues can be sufficient to generate specific synaptic circuitry.