中国神经再生研究(英文版) ›› 2020, Vol. 15 ›› Issue (12): 2353-2361.doi: 10.4103/1673-5374.284999

• 原著:周围神经损伤修复保护与再生 • 上一篇    下一篇

周围神经轴突切断后早期FOXO3a表达缺失有助于减轻感觉神经元损伤

  

  • 出版日期:2020-12-15 发布日期:2020-08-05
  • 基金资助:
    加拿大卫生研究院(CIHR)以及加拿大自然科学与科学与工程研究委员会的资助;萨斯喀彻温大学研究生和博士后奖学金的支持。

FOXO3a as a sensor of unilateral nerve injury in sensory neurons ipsilateral, contralateral and remote to injury

Jovan C.D. Hasmatali 1, 2, 3, Jolly De Guzman 1, 2 , Jayne M. Johnston 1, 2 , Hossein Noyan 1, 2, Bernhard H. Juurlink 1, 2 , Vikram Misra 3 , Valerie M.K. Verge 1, 2   

  1. 1 Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada
    2 Cameco MS Neuroscience Research Center, University of Saskatchewan, Saskatoon, SK, Canada
    3 Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, SK, Canada
  • Online:2020-12-15 Published:2020-08-05
  • Contact: Valerie M.K. Verge, PhD,valerie.verge@usask.ca.
  • Supported by:
    This work was supported by Canadian Institutes of Health Research (CIHR) grants #74747 and #14238 (both to VMKV) and by a Natural Sciences and Science and Engineering Research Council (NSERC) of Canada grant (to VM). JCDH was supported by University of Saskatchewan College of Graduate and Postdoctoral Studies Scholarships.

摘要:

已有证据表明,神经损伤的应激反应超出了受损神经元承受能力时,病变的局部和远处均可检测到相关转录因子的改变。应激诱导的转录因子FOXO3a的核易位与许多神经元凋亡基因的激活有关。为验证FOXO3a在受损的感觉神经元中表达的数量,以及未损伤的感觉神经元是否也改变了FOXO3a的表达,实验观察了单侧腰4-6节段脊神经横断对成年大鼠背根神经节(DRG)同侧、对侧或远端神经元中FOXO3a表达和核定位时间的影响。(1)在未损伤神经元中,细胞质和细胞核中FOXO3a的高表达与降钙素基因相关肽共定位。伤后1h,受伤的小神经元胞核中FOXO3a表达急剧增加,在伤后1,2和4d后明显下降,至伤后1周逐渐升高至损伤前水平。(2)在损伤脊神经对侧和远离损伤脊神经的未受伤背根神经节神经元中,观察到了更强的损伤应激双相反应。脊神经元胞核FOXO3a表达在受伤后第1天达到峰值,随后4d减少,伤后1周时增加,这种反应在远离损伤的颈4节段背根神经节神经元中有存在。(3)总之,实验结果为进一步了解单侧脊神经损伤后FOXO3a的表达变化对背根神经节神经元的影响开拓了视野。

orcid: 0000-0001-6648-3242 (Valerie M. K. Verge)

关键词: 单侧周围神经损伤, 细胞体反应, 对侧反应, 背根神经节, 周围神经损伤, 可塑性, 坐骨神经, 感觉神经元, 应激, 系统性, 转录因子

Abstract: 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 ini- tially 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 expres- sion 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-in- jury. 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).

Key words: cell body response, contralateral response, dorsal root ganglion, peripheral nerve injury, plasticity, sciatic nerve, sensory neuron, stress, systemic, transcription factor, unilateral peripheral nerve injury