Lin28/let-7 pathway regulates metabolic activity and neuronal excitability in response to peripheral nerve injury

Genome-wide sensory neuron-specific and nociceptor-enriched profiling of miRNA:target RNA interactions, achieved using the Nav1.8 promoter, reveals abundant let-7 miRNA targeting of metabolic transcripts in healthy sensory axons which is diminished by nerve injury. Injured sciatic nerves exhibit disrupted cellular respiration near the site of nerve injury which can be 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 both spared ipsilateral peripheral sensory neurons and spinal cord dorsal horn neurons.

These results implicate the Lin28/let-7 pathway as a critical driver of metabolic dysregulation and heightened sensory nervous system activity following nerve injury.