Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun

Abstract:

ABSTRACT After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during the chronic denervation that results from the slow growth of axons. This impairs axonal regeneration and causes a significant clinical problem. In mice, we find that repair cells express reduced c-Jun protein as the regenerative support provided by these cells declines in aging animals and during chronic denervation. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to that in controls. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. This establishes that a common mechanism, reduced c-Jun in Schwann cells, regulates the success and failure of nerve repair both during aging and chronic denervation. This provides a molecular framework for addressing important clinical problems, and suggests molecular pathways that can be targeted to promote repair in the PNS.