Locally synthesized calcitonin gene-related Peptide has a critical role in peripheral nerve regeneration

Regeneration of peripheral nerves involves complex and intimate interactions between axons and Schwann cells. Here, we show that local axon synthesis and action of the neuropeptide calcitonin gene-related peptide (CGRP) is critical for this collaboration. After peripheral sural sensory axon injury in rats, we observed an unexpectedly large proportion of axons that newly expressed CGRP during regeneration. Intense peptide expression accompanied local rises in alphaCGRP mRNA in the nerve trunk, and there was evidence of transport of alphaCGRP mRNA into regenerating axons, indicating intra-axonal peptide synthesis. Calcitonin gene-related peptide receptor and its receptor activity modifying protein were expressed onadjacent Schwann cells, where they were available for signaling. Moreover, exogenous CGRP induced proliferation in isolated adult Schwann cells. New axon outgrowth and CGRP expression depended on local peptide synthesis and were inhibited by exposure tolocal translation inhibitors. Local delivery of siRNAs to either alphaCGRP or receptor activity modifying protein 1 to sites of nerve transection was associated with severe disruption of axon outgrowth.These findings indicate that robust localized intra-axonal translation of the CGRP neuropeptide during regeneration signals Schwann cell proliferation, behavior that is critical for partnering during adult peripheral nerve regrowth.