Ribonuclease 4 Functions in Nociceptor-Mediated Nerve Homeostasis

The regulation of nociceptor identity and function is essential, as disruptions can significantly influence pain sensation, yet our understanding of the molecular mechanisms involved remains incomplete. In this study, we identified ribonuclease 4 (RNase4) as selectively expressed in the unmyelinated nociceptor lineage. Analysis of Rnase4-deficient mice and single-cell transcriptomic data revealed a cell-autonomous role for RNase4 in regulating nociceptor function. Moreover, in a neuropathic pain model, Rnase4 expression was upregulated in nociceptors during the pain and recovery phases, and its deletion altered mechanical sensation. Additionally, RNase4 exerted non-cell autonomous effects on the structural organization of adjacent myelinated axons. These findings suggest that RNase4 contributes to nociceptor biology and point to a pathway for further investigation of pain regulation. Overall design: Following tamoxifen injection DAPI+NeuN+ stained nuclei from dorsal root ganglia were isolated using fluoresence activate cell sorting (FACS) and analyzed using snRNA-seq.