# Ribonuclease 4 Functions in Nociceptor-Mediated Nerve Homeostasis

## TL;DR

This study shows that ribonuclease 4 helps regulate pain-sensing nerve cells and supports nerve repair by maintaining nerve stability.

## Contribution

The study identifies RNase4 as a dual regulator of nociceptor function and myelin integrity.

## Key findings

- RNase4 is selectively expressed in unmyelinated nociceptors and regulates their function.
- RNase4 deletion alters mechanical sensation and affects myelin structure in adjacent axons.
- RNase4 expression increases during pain and recovery phases in a neuropathic model.

## Abstract

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 myelin structural organization of adjacent myelinated axons. Together, these findings implicate RNase4 as a dual regulator of nociceptor biology and myelin integrity, revealing a molecular pathway for pain regulation and nerve repair.

In this study, the authors find that ribonuclease 4 (RNase4)-expressing nociceptors, through RNase4, act as regulatory hubs that maintain peripheral nerve stability and coordinate nerve responses to injury, revealing a homeostatic role for nociceptors.