García-Bejarano Marina, Aucello Riccardo, Zen Federica, El Soury Marwa, Cordero Francesca, de la Fuente Jesús M, Perroteau Isabelle, Ronchi Giulia, Gambarotta Giovanna
Department of Clinical and Biological Sciences (DSCB), University of Torino, Orbassano, Italy.
Neuroscience Institute Cavalieri Ottolenghi (NICO ), University of Torino, Orbassano, Italy.
Front Cell Dev Biol. 2025 Mar 27;13:1540453. doi: 10.3389/fcell.2025.1540453. eCollection 2025.
Regulators of G Protein Signaling (RGS) form a gene family that modulates G protein-coupled receptor signaling by enhancing the GTPase activity of the Gα-GTP complex, effectively inhibiting G protein-dependent signal transduction cascades. While RGSs are expressed across many organs, including the central nervous system, few data are available for the peripheral nervous system (PNS). To investigate potential links between RGS and PNS, open-access single-cell RNA sequencing datasets were analyzed, focusing on mice intact sciatic nerves and distal stumps at 3 and 9 days post-transection. emerged as the RGS member most highly expressed by Schwann cells after injury, suggesting its involvement in nerve degeneration. To further explore behavior in nerve injury, its expression was assessed at mRNA level at different time points in the median nerve of adult rats under regenerating conditions following mild (crush) or more severe (end-to-end repair) traumatic injury, and under degenerating conditions. Results revealed that expression increased 3 days after injury, declining under regenerating conditions, but remaining high in degenerating conditions. To examine the role of in chronic nerve degeneration, its expression was evaluated in a pathological model of Charcot-Marie-Tooth disease type-1A (CMT1A), a chronic demyelinating peripheral neuropathy. Analysis of publicly available RNA sequencing data from sciatic nerves of wild-type and CMT1A rats during development showed a significant upregulation of in transgenic rats at P18. Interestingly, this upregulation mirrored the expression pattern of Neuregulin1 (), a gene critical for Schwann cell dedifferentiation and demyelination, strongly upregulated in traumatic and chronic nerve injuries. To explore a potential NRG1-RGS16 link, primary Schwann cell cultures were treated with recombinant NRG1β1, which induced an increase in expression. These findings suggest a potential feedback mechanism where transient upregulation in response to injury and/or NRG1 might negatively regulate NRG1 release through RGS16-mediated inhibition of GPCR/ErbB transactivation. This study highlights the dynamic role of in traumatic and chronic nerve injuries, implicating its involvement in processes of nerve degeneration, regeneration, and possibly neuropathic pain. Further investigations are needed to clarify RGS16 function, which could pave the way for novel therapeutic strategies to enhance nerve regeneration and alleviate neuropathic pain.
G蛋白信号调节因子（RGS）构成一个基因家族，通过增强Gα-GTP复合物的GTP酶活性来调节G蛋白偶联受体信号传导，从而有效抑制G蛋白依赖性信号转导级联反应。虽然RGS在包括中枢神经系统在内的许多器官中都有表达，但关于外周神经系统（PNS）的数据却很少。为了研究RGS与PNS之间的潜在联系，分析了开放获取的单细胞RNA测序数据集，重点关注小鼠完整坐骨神经以及横断后3天和9天的远端残端。RGS16成为损伤后施万细胞中表达最高的RGS成员，表明其参与神经退变。为了进一步探究RGS16在神经损伤中的作用，在成年大鼠正中神经轻度（挤压）或更严重（端端修复）创伤性损伤后的再生条件下以及退变条件下，在不同时间点对其mRNA水平的表达进行了评估。结果显示，RGS16的表达在损伤后3天增加，在再生条件下下降，但在退变条件下仍保持高水平。为了研究RGS16在慢性神经退变中的作用，在1A型遗传性运动感觉神经病（CMT1A）（一种慢性脱髓鞘性周围神经病）的病理模型中评估了其表达。对野生型和CMT1A大鼠发育过程中坐骨神经的公开可用RNA测序数据进行分析，结果显示在P18时转基因大鼠中RGS16显著上调。有趣的是，这种上调反映了神经调节蛋白1（NRG1）的表达模式，NRG1是施万细胞去分化和脱髓鞘的关键基因，在创伤性和慢性神经损伤中强烈上调。为了探究潜在的NRG1-RGS16联系，用重组NRG1β1处理原代施万细胞培养物，这导致RGS16表达增加。这些发现提示了一种潜在的反馈机制，即损伤和/或NRG1引起的RGS16短暂上调可能通过RGS16介导的GPCR/ErbB反式激活抑制来负向调节NRG1释放。本研究突出了RGS16在创伤性和慢性神经损伤中的动态作用，表明其参与神经退变、再生过程，可能还参与神经性疼痛。需要进一步研究以阐明RGS16的功能，这可能为增强神经再生和减轻神经性疼痛的新治疗策略铺平道路。
