Polysialylated neural cell adhesion molecule is necessary for selective targeting of regenerating motor neurons

It is well established that peripheral nerves regenerate after injury. Therefore, incomplete functional recovery usually results from misguided axons rather than a lack of regeneration per se. Despite this knowledge very little is known about the molecular mechanisms regulating axon guidance during regeneration. In the developing neuromuscular system the neural cell adhesion molecule (NCAM) and its polysialic acid (PSA) moiety are essential for proper motor axon guidance. In this study we used a well established model of nerve transection and repair to examine whether NCAM and/or PSA promotes selective regeneration of femoral motor nerves in wild-type and NCAM (-/-) mice. We found that regenerating axons innervating the muscle pathway and, to a lesser extent, cutaneous axons in the sensory pathway reexpress high levels of PSA during the time when the cut axons are crossing the lesion site. Second, we found that motor neurons in wild-type mice preferentially reinnervated muscle pathways, whereas motor neurons in NCAM (-/-) mice reinnervated muscle and cutaneous pathways with equal preference. Preferential regeneration was not observed in wild-type mice when PSA was removed enzymatically from the regenerating nerve, indicating that this form of selective motor axon targeting requires PSA. Finally, transgenic mice were used to show that the number of collateral sprouts, their field of arborization, and the withdrawal of misprojected axons were all attenuated significantly in mice lacking PSA. These results indicate that regenerating motor axons must express polysialylated NCAM, which reduces axon-axon adhesion and enables motor neurons to reinnervate their appropriate muscle targets selectively.