When peripheral motor axons are damaged, they have what seems to be a remarkable ability to regenerate and reconnect with the muscle target that they innervated before injury. In fact, as Nguyen et al. show in a new paper in Nature Neuroscience, the reinnervation process is even more accurate than was previously thought, and many axons actually re-establish contact with their original neuromuscular junction (NMJ). However, the explanation for this phenomenon is not as complex as one might imagine — the results of this study indicate that the axons simply retrace their original path.

The authors used a mouse line in which a fraction of motor axons expressed yellow or cyan fluorescent proteins, and they also visualized the NMJs using bungarotoxin. They crushed the axon fibres that innervate the sternomastoid or platysma muscles of the neck, and then observed the paths taken by the regenerating axons. In more than 90% of cases, the axons not only reinnervated their original NMJs, but also re-established their original branching patterns.

One explanation for this finding is that the specific molecular cues that guided the axon during development were still in place, and the axon used them to recapitulate this process. However, the authors favour a much simpler explanation. A key feature of a crush injury is that the endoneurial tubes — cylindrical arrays of non-neuronal cells that surround the nerve fibres — remain intact. If the nerve is cut, on the other hand, the endoneurial tubes are damaged, and the re-targeting of axons is much less accurate. This indicates that intact endoneurial tubes are required for axon guidance during repair. Also, Nguyen et al. showed that, on the rare occasions when an axon entered the wrong pathway, it followed exactly the same route as the axon that was present before injury, indicating that the guidance cues are not axon-specific.

The authors suggest that a nonspecific mechanical cue might be important for axon guidance during repair. Rather than following a complex array of specific molecular cues, the axons simply grow down a pre-existing tubular network. As recent studies on axon guidance have tended to focus on molecular mechanisms, it is possible that the importance of mechanical cues has been underestimated, and this study by Nguyen et al. goes some way towards redressing the balance.