Peripheral nerve injury alters metabolic function and neuronal excitability through the Lin28/let-7 pathway.

Sensory neurons require efficient metabolic processes to reliably transmit information including touch, temperature, and noxious stimuli from peripheral to central nervous systems. Peripheral nerve injury is known to disrupt metabolic function resulting in aberrant sensory nervous system excitation, but molecular pathways linking nerve injury to persistent alterations in metabolism and neuronal activity have been incompletely understood. We find that a conserved metabolic regulator, RNA binding protein Lin28, is elevated in the somas of dorsal root ganglion (DRG) nociceptive neurons following nerve injury but exhibits a higher and more enduring local induction in peripheral sensory axons of the injured nerve. Growth suppressor let-7 family microRNAs (miRNAs), whose biogenesis is inhibited by Lin28, are down-regulated following injury, consistent with the spatiotemporal course of Lin28 induction. Genome-wide sensory neuron-specific and nociceptor-enriched profiling of miRNA:target RNA interactions reveals abundant let-7 miRNA targeting of metabolic transcripts in healthy sensory axons, which is diminished by nerve injury. Consistently, injured sciatic nerves exhibit disrupted cellular respiration near the site of nerve injury, which is alleviated by local restoration of let-7 miRNAs. Selective Lin28 knockout in nociceptive sensory neurons also alleviates the metabolic disturbances of nerve injury as well as suppressing injury-induced elevation of activity in ipsilateral peripheral sensory neurons and central spinal cord dorsal horn neurons. These results implicate the Lin28/let-7 pathway as a critical driver of metabolic dysregulation and the pathophysiology of heightened sensory nervous system activity following nerve injury.