Work

The RNA-binding protein CELF4 is a negative regulator of sensory neuron excitability and mechanical and heat behavioral sensitivity

Year: 2025

Type: article

Abstract: • This paper addresses the function of the mRNA translation regulator, CELF4, in behavioral sensitivity, hyperalgesia, and sensory neuron excitability. • We show that this RNA-binding protein is a robust tonic negative regulator of nociceptor excitability, that may act as an endogenous brake on the development of hyperalgesia • Targeting CELF4 may lead to the discovery of mechanisms that regulate nociceptor-intrinsic de novo protein synthesis and further our understanding of the transition to chronic pain. RNA-binding proteins (RBPs) regulate gene function by controlling RNA processing, transport, stability, and translation. Recent mechanistic and pre-clinical studies demonstrate that nociceptive sensitivity and plasticity are regulated by RNA-protein interactions. Investigating RBP function in sensory neurons may reveal new strategies to modulate nociceptor excitability and/or sensitivity and improve our understanding of mechanisms that contribute to pain chronification. We previously identified the RBP CUG triplet repeat binding protein ( C UGBP) embryonic lethal abnormal vision ( E lav)- l ike f amily member 4 (CELF4) as co-expressed with nociceptive markers in mouse, rat, and macaque dorsal root ganglia (DRG). In the central nervous system, CELF4 limits the translation of synaptic mRNAs, and loss of CELF4 results in hyperexcitability of excitatory neurons and spontaneous seizures. To elucidate the function of CELF4 in sensory neurons, we employed conditional knockout (KO) mouse models, with Celf4 deleted selectively in populations of adult DRG neurons. Using patch-clamp electrophysiology in acutely dissociated neurons, we observed a striking reduction in rheobase and hyperexcitability of capsaicin-sensitive adult Celf4 KO DRG neurons compared to controls. Behavioral assessments revealed that these mice display robust mechanical and thermal hypersensitivity and an exaggerated evoked hypersensitivity response to intraplantar capsaicin and nerve growth factor. These studies reveal that the translational regulator CELF4 is a powerful negative regulator of sensory neuron excitability and sensory thresholds to heat and mechanical stimuli resulting in thermal and mechanical hypersensitivity in uninjured mice and exacerbating hypersensitivity in injured mice. These findings elucidate a novel mechanism for modulating sensory neuron excitability with high specificity to putative nociceptors.

Source: Neurobiology of Pain

DOI: 10.1016/j.ynpai.2025.100184