The specificity of motor neurone regeneration (preferential reinnervation)

The major determinant of functional recovery after lesions in the peripheral nervous system is the accurate regeneration of axons to their original target end‐organs. Unfortunately, regenerating motor axons are often misrouted to sensory target end‐organs, and sensory axons formerly innervating skin are often misrouted to muscle. As such regeneration is robust, but often inaccurate, a better understanding of how regenerating axons reinnervate terminal pathways would be of fundamental interest to basic and clinical neuroscience. This review will consider the underlying cellular and molecular mechanisms that influence the accuracy of peripheral nerve regeneration, within the context of ‘preferential motor reinnervation’ (PMR). Much previous work with PMR has utilized the rodent femoral nerve and has shown that regenerating motor axons preferentially, albeit incompletely, reinnervate a distal terminal nerve branch to muscle (quadriceps) vs. skin (saphenous). One interpretation of this body of work has been that Schwann cell tubes have a specific identity that can be recognized by regenerating motor axons and that influences their subsequent behaviour. We disagree with that interpretation, and suggest motor and cutaneous pathways are not inherently different in terms of their ability to support regeneration of motor axons. In fact, recent experiments indicate under certain conditions motor axons will preferentially reinnervate the inappropriate terminal cutaneous pathway instead of the appropriate pathway to muscle. We suggest that it is the relative level of trophic support provided by each nerve branch that determines whether motor axons will remain in that particular branch. Within the context of the femoral nerve model, our results suggest a hierarchy of trophic support for regenerating motor axons with muscle contact being the highest, followed by the length of the terminal nerve branch and/or contact with skin.