Following peripheral nerve injury, myelin and Remak Schwann cells up-regulate a repair phenotype, controlled by c-Jun, to facilitate axon regeneration. Despite activation of this phenotype, nerve regeneration in humans is poor. An important factor is the deterioration of the distal nerve stump, a process involving a decrease in trophic factors initially up-regulated following injury and a decline in Schwann cell numbers, resulting in poor long-term regeneration. Regeneration deficits also develop with age - injured nerves in old mice regenerate slowly. I hypothesized that in old mice, and during chronic denervation, c-Jun levels are not maintained. This predicts that in young mice, c-Jun levels fall during chronic denervation, and that by maintaining Schwann cell c-Jun, the deterioration of the distal stump can be prevented. Similarly, by enhancing c-Jun levels in old mice, the regeneration deficit should be reversed. In young mice, Schwann cell c-Jun significantly decreased during chronic denervation. Markers of the repair phenotype also declined. A mouse that over-expressed Schwann cell c-Jun (OE/+) was generated. Following chronic denervation, Schwann cells in denervated nerves maintained c-Jun levels. Regeneration was assessed by suturing a chronically denervated tibial nerve to a freshly cut common peroneal nerve, followed by neuronal backfilling. Improved motor and sensory neuron regeneration was observed in OE/+ mice following chronic denervation. In old OE/+ mice, the reduced c-Jun levels seen in old wild type mice were corrected. Regeneration was assessed by backfilling and old OE/+ nerves maintained the regenerative capacity of young animals. These results highlighted c-Jun as a pharmaceutical target. Sonic hedgehog is elevated after nerve injury and agonists significantly increased c-Jun and trophic factor expression in cultured Schwann cells. This work implicates the c-Jun pathway in the regeneration deficit that occurs following chronic denervation and with advancing age, and highlights hedgehog signalling as an activator of c-Jun
