Madison G. Mueth , Peter Neufeld , Merilla Michael , Aidan McGrath-Conwell , Eliza Grlickova-Duzevik , Tamara King , Christoph Straub , Benjamin J. Harrison
{"title":"rna结合蛋白CELF4是感觉神经元兴奋性、机械和热行为敏感性的负调节因子","authors":"Madison G. Mueth , Peter Neufeld , Merilla Michael , Aidan McGrath-Conwell , Eliza Grlickova-Duzevik , Tamara King , Christoph Straub , Benjamin J. Harrison","doi":"10.1016/j.ynpai.2025.100184","DOIUrl":null,"url":null,"abstract":"<div><div>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 (<u>C</u>UGBP) embryonic lethal abnormal vision (<u>E</u>lav)-<u>l</u>ike <u>f</u>amily member <u>4</u> (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 <em>Celf4</em> 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 <em>Celf4</em> 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.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"18 ","pages":"Article 100184"},"PeriodicalIF":0.0000,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The RNA-binding protein CELF4 is a negative regulator of sensory neuron excitability and mechanical and heat behavioral sensitivity\",\"authors\":\"Madison G. Mueth , Peter Neufeld , Merilla Michael , Aidan McGrath-Conwell , Eliza Grlickova-Duzevik , Tamara King , Christoph Straub , Benjamin J. Harrison\",\"doi\":\"10.1016/j.ynpai.2025.100184\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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 (<u>C</u>UGBP) embryonic lethal abnormal vision (<u>E</u>lav)-<u>l</u>ike <u>f</u>amily member <u>4</u> (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 <em>Celf4</em> 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 <em>Celf4</em> 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.</div></div>\",\"PeriodicalId\":52177,\"journal\":{\"name\":\"Neurobiology of Pain\",\"volume\":\"18 \",\"pages\":\"Article 100184\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-05-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neurobiology of Pain\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2452073X25000066\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurobiology of Pain","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2452073X25000066","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0
摘要
RNA结合蛋白(rbp)通过控制RNA加工、转运、稳定性和翻译来调节基因功能。最近的机制和临床前研究表明,伤害性敏感性和可塑性是由rna -蛋白相互作用调节的。研究RBP在感觉神经元中的功能可能揭示调节伤害感受器兴奋性和/或敏感性的新策略,并提高我们对疼痛慢性化机制的理解。我们之前在小鼠、大鼠和猕猴背根神经节(DRG)中发现了RBP CUG三联体重复结合蛋白(CUGBP)胚胎致死性异常视力(Elav)样家族成员4 (CELF4)与伤害性标志物共表达。在中枢神经系统中,CELF4限制了突触mrna的翻译,CELF4的缺失导致兴奋性神经元的高兴奋性和自发性癫痫发作。为了阐明CELF4在感觉神经元中的功能,我们采用了条件敲除(KO)小鼠模型,在成年DRG神经元群体中选择性地删除CELF4。利用膜片钳电生理学对急性解离神经元进行观察,我们发现与对照相比,辣椒素敏感的成人cellf4 KO DRG神经元的流变酶和高兴奋性显著降低。行为评估显示,这些小鼠表现出强烈的机械和热超敏反应,并对足底辣椒素和神经生长因子表现出夸大的诱发超敏反应。这些研究表明,翻译调节因子CELF4是一个强大的感觉神经元兴奋性和感觉阈值对热和机械刺激的负调节因子,导致未损伤小鼠的热和机械超敏反应,并加剧损伤小鼠的超敏反应。这些发现阐明了一种调节感觉神经元兴奋性的新机制,该机制对假定的伤害感受器具有高特异性。
The RNA-binding protein CELF4 is a negative regulator of sensory neuron excitability and mechanical and heat behavioral sensitivity
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 (CUGBP) embryonic lethal abnormal vision (Elav)-like family 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.