Hasmatali Jovan C D, De Guzman Jolly, Johnston Jayne M, Noyan Hossein, Juurlink Bernhard H, Misra Vikram, Verge Valerie M K
Department of Anatomy, Physiology, and Pharmacology; Cameco MS Neuroscience Research Center; Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, SK; Current affiliation: Department of Critical Care Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
Department of Anatomy, Physiology, and Pharmacology; Cameco MS Neuroscience Research Center, University of Saskatchewan, Saskatoon, SK, Canada.
Neural Regen Res. 2020 Dec;15(12):2353-2361. doi: 10.4103/1673-5374.284999.
Emerging evidence supports that the stress response to peripheral nerve injury extends beyond the injured neuron, with alterations in associated transcription factors detected both locally and remote to the lesion. Stress-induced nuclear translocation of the transcription factor forkhead class box O3a (FOXO3a) was initially linked to activation of apoptotic genes in many neuronal subtypes. However, a more complex role of FOXO3a has been suggested in the injury response of sensory neurons, with the injured neuron expressing less FOXO3a. To elucidate this response and test whether non-injured sensory neurons also alter FOXO3a expression, the temporal impact of chronic unilateral L4-6 spinal nerve transection on FOXO3a expression and nuclear localization in adult rat dorsal root ganglion neurons ipsilateral, contralateral or remote to injury relative to naïve controls was examined. In naïve neurons, high cytoplasmic and nuclear levels of FOXO3a colocalized with calcitonin gene related peptide, a marker of the nociceptive subpopulation. One hour post-injury, an acute increase in nuclear FOXO3a in small size injured neurons occurred followed by a significant decrease after 1, 2 and 4 days, with levels increasing toward pre-injury levels by 1 week post-injury. A more robust biphasic response to the injury was observed in uninjured neurons contralateral to and those remote to injury. Nuclear levels of FOXO3a peaked at 1 day, decreased by 4 days, then increased by 1 week post-injury, a response mirrored in C4 dorsal root ganglion neurons remote to injury. This altered expression contralateral and remote to injury supports that spinal nerve damage has broader systemic impacts, a response we recently reported for another stress transcription factor, Luman/CREB3. The early decreased expression and nuclear localization of FOXO3a in the injured neuron implicate these changes in the cell body response to injury that may be protective. Finally, the broader systemic changes support the existence of stress/injury-induced humeral factor(s) influencing transcriptional and potentially behavioral changes in uninjured dorsal root ganglion neurons. Approval to conduct this study was obtained from the University of Saskatchewan Animal Research Ethics Board (protocol #19920164).
新出现的证据表明，对周围神经损伤的应激反应不仅局限于受损神经元，在损伤部位局部和远处均检测到相关转录因子的改变。应激诱导的转录因子叉头框O3a（FOXO3a）的核转位最初与许多神经元亚型中凋亡基因的激活有关。然而，在感觉神经元的损伤反应中，FOXO3a的作用更为复杂，受损神经元中FOXO3a的表达较少。为了阐明这种反应，并测试未受损的感觉神经元是否也会改变FOXO3a的表达，研究了成年大鼠慢性单侧L4-6脊神经横断相对于未处理对照组，对同侧、对侧或远离损伤部位的背根神经节神经元中FOXO3a表达和核定位的时间影响。在未处理的神经元中，高细胞质和核水平的FOXO3a与降钙素基因相关肽共定位，降钙素基因相关肽是伤害性亚群的标志物。损伤后1小时，小型受损神经元中核FOXO3a急性增加，随后在1、2和4天后显著下降，损伤后1周时水平恢复至损伤前水平。在与损伤部位对侧和远离损伤部位的未受损神经元中，观察到对损伤的更强双相反应。FOXO3a的核水平在损伤后1天达到峰值，4天后下降，然后在损伤后1周增加，在远离损伤部位的C4背根神经节神经元中也观察到这种反应。损伤对侧和远离损伤部位的这种表达改变支持脊神经损伤具有更广泛的全身影响，这是我们最近报道的另一种应激转录因子Luman/CREB3的反应。受损神经元中FOXO3a早期表达和核定位的降低表明这些变化参与了细胞体对损伤的反应，可能具有保护作用。最后，更广泛的全身变化支持存在应激/损伤诱导的体液因子，影响未受损背根神经节神经元的转录和潜在行为变化。本研究已获得萨斯喀彻温大学动物研究伦理委员会的批准（协议编号#19920164）。
