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

ABSTRACT: Sensory neurons rely on efficient metabolic processes to reliably transmit information including touch, temperature, and noxious stimuli from the peripheral to central nervous systems. Metabolic dysfunction downstream of peripheral nerve injury is central to the generation of consequent sensory nervous system hyperexcitability, but molecular pathways linking nerve injury to persistent alterations in metabolism and neuronal activity are incompletely understood. We find that transcripts for the conserved metabolic regulator, RNA-binding protein Lin28, are elevated in the soma of dorsal root ganglion (DRG) nociceptive neurons following nerve injury, but exhibit a higher and more enduring induction in peripheral sensory axons of the injured nerve. Growth-suppressor let-7 family microRNAs (miRNAs), whose biogenesis is inhibited by Lin28, are downregulated following injury, consistent with the spatiotemporal course of Lin28 induction. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE320207 | GEO | 2026/09/03

REPOSITORIES: GEO