Polysialic acid expression is not necessary for motor neuron target selectivity.

When a peripheral nerve is repaired after injury, regenerating axons may or may not reestablish functional connections with their original end-organ targets. Although the capacity for regrowth is robust, functional recovery is often poor.1 The key to obtaining functional recovery is the accurate regeneration of axons to their original end-organ targets. Any therapeutic intervention that enhances the accuracy of nerve regeneration and functional recovery after such nerve lesions would be a welcome change from the current, severely limited, recovery; permanent functional compromise occurs in up to 90% of adult nerve repairs.2-4 Because the finest sutures and needles available to peripheral nerve surgeon are still considerably larger than the size of axons to be repaired, the limits of microsurgical techniques have been reached. In order to develop intervention strategies that will increase regeneration accuracy, there will need to be a greater understanding of the basic cellular and molecular events that influence axonal growth choices within the complex in vivo environment of peripheral nerves. The proximal femoral nerve contains a mixed population of motor and sensory axons, but as these axons course more distally they are progressively segregated into 2 anatomically distinct pathways of approximately equal size that project either to the quadriceps femoris muscle or to the skin via the saphenous nerve.2,5 The rodent femoral nerve has been a useful model for in vivo studies of nerve regeneration. It was originally introduced in 1945 by Weiss and Edds6 as a model system to study the fate of axons that originally innervated muscle or skin when they were forcibly misdirected into the inappropriate nerve branch. The original femoral nerve model was modified by the Brushart laboratory to examine the fate of regenerating motor neurons when they were given equal access to the terminal cutaneous and muscle branches rather than being forced into foreign nerve stumps.2,3 Subsequent work at several different laboratories demonstrated that, after a proximal lesion of the parent femoral nerve, regenerating motor neurons preferentially reinnervate the terminal nerve branch to muscle versus the terminal cutaneous branch.7-11 In addition to the possibility of inherent pathway differences that might be responsible for motor neuron regeneration accuracy, it has been suggested recently that intrinsic differences that exist between motor neuron pools themselves might control selective targeting of regenerating motor neurons at a lesion site of a mixed peripheral nerve. Franz et al.5,12 suggested that polysialic acid (PSA) is a necessary requirement for motor neuron regeneration accuracy. Those motor neuron pools that are able to express PSA can accurately reinnervate a muscle pathway, and those motor neuron pools that do not express PSA do not. We show here, however, that a simple surgical manipulation of a terminal nerve pathway dramatically influences the ability of motor neurons to correctly reinnervate a terminal nerve to muscle, regardless of neuronal PSA expression. This is further evidence that motor neuron regeneration accuracy is not determined solely by specific molecular signatures of either the motor neuron itself or the terminal nerve pathway. Rather, we suggest it is the relative levels of trophic support available in each terminal pathway that is the limiting factor that determines whether motor neurons will display regeneration accuracy, a general process that has been termed trophomorphism.13,14