中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (10): 5063-5070.doi: 10.4103/NRR.NRR-D-25-00034

• 原著:视神经损伤修复保护与再生 • 上一篇    下一篇

热休克蛋白40促进创伤性视神经病变轴突再生

  

  • 出版日期:2026-10-15 发布日期:2026-06-15

Heat shock protein 40 enhances axon regeneration in a mouse model of traumatic optic neuropathy

Jiaxing Wang1, Ying Li1, Felix L. Struebing1, 2, Sandra Jardines1, Su-Ting Lin1, Fangyu Lin1, Eldon E. Geisert1, *   

  1. 1Department of Ophthalmology, Emory University, Atlanta, GA, USA;  2Center for Neuropathology and Prion Research, Ludwig Maximilian University of Munich, Munich, Germany
  • Online:2026-10-15 Published:2026-06-15
  • Contact: Eldon E. Geisert, PhD, egeiser@emory.edu.
  • Supported by:
    This study was supported by grants from the BrightFocus Foundation G2019111 (to EEG) and G20220125 (to JW), Owens Family Glaucoma Research Fund, NEI grant R01EY031042 (to EEG), P30EY06360 (Machelle Pardue), Challenge Grant from Research to Prevent Blindness (Allen Beck), NIH/NCU grant P30CA138292 (Emory Integrated Genomics Core), and Emory Viral Vector Core  https://neurology.emory.edu/ENNCF/viral_vector/).

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摘要：

视网膜神经节细胞死亡发生于视神经受损后，无论是创伤还是青光眼等疾病，均会导致严重视力丧失。近期研究表明视神经再生是可行的，但再生程度有限。为识别促进轴突再生的基因组元件，实验采用正向遗传学方法，利用BXD重组小鼠品系识别可增加视神经再生程度的基因。通过腺相关病毒递送shRNA敲低视网膜神经节细胞中的Pten，随后进行玻璃体腔注射Zymosan与CPT-cAMP（引发轻微炎症反应）以诱导轴突再生。视网膜神经节细胞轴突通过视神经挤压损伤。经过12天的生存期后，通过玻璃体腔注射与Alexa Fluor 647偶联的霍乱毒素B对再生轴突进行标记。两天后，对视神经内标记的轴突进行检测，以确定再生轴突的数量及其沿视神经行进的距离。分析结果显示，在所有33个BXD品系中，轴突再生程度存在显著差异。再生轴突的数量存在7.5倍的差异，而再生轴突的移动距离存在4倍的差异。这些数据被用于生成一个间隔图谱，以定义调节增强轴突再生能力的基因组位点。在第14号染色体（115至119 Mb）上识别出一个调节轴突再生的数量性状位点。该位点内包含16个注释基因。后续测试揭示，其中一个候选基因Dnajc3可调节轴突再生。Dnajc3编码热休克蛋白40，这是一种分子伴侣。在高再生能力品系（BXD90）中敲低Dnajc3导致再生反应降低；而在低再生能力品系（BXD34）中过表达Dnajc3则导致再生反应增强。这些发现表明，Dnajc3不仅增加再生轴突的数量，还增加这些轴突的行进距离。增强的再生能力对人类功能恢复至关重要，因为人类轴突到达目标的距离远长于小鼠。


https://orcid.org/0000-0003-0787-4416 (Eldon E. Geisert)

关键词: 基因组学, 复杂性状, 轴突再生, 视神经, Dnajc3, 热休克蛋白40, 视网膜神经节细胞, 小鼠, 神经再生

Abstract: Retinal ganglion cell death occurs following injury to the optic nerve either by trauma or in disease such as glaucoma, leading to severe vision loss. Recent innovations have demonstrated that optic nerve regeneration is feasible; however, the regeneration is limited. The aim of the present study is to identify genomic elements enhancing axon regeneration. We have taken a forward genetics approach using the BXD recombinant mouse strains to identify a gene that increases the extent of optic nerve regeneration. Axon regeneration was induced by knocking down Pten in retinal ganglion cells using adeno-associated virus to deliver an shRNA followed by an intravitreal injection of Zymosan with CPT-cAMP that produced a mild inflammatory response. Retinal ganglion cell axons were damaged by optic nerve crush. Following a 12-day survival period, regenerating axons were labeled by intravitreal injection of Cholera Toxin B conjugated with Alexa Fluor 647. Two days later, labeled axons within the optic nerve were examined to determine the number of regenerating axons and the distance they traveled down the optic nerve. The analysis revealed a surprising difference in the amount of axonal regeneration across all 33 BXD strains. There was a 7.5-fold difference in the number of regenerating axons and a 4-fold difference in the distance traveled by regenerating axons. These data were used to generate an interval map defining genomic loci that modulate enhanced axonal regeneration. A quantitative trait locus modulating axon regeneration was identified on Chromosome 14 (115 to 119 Mb). Within this locus were 16 annotated genes. Subsequent testing revealed that one candidate gene, Dnajc3, modulated axonal regeneration. Dnajc3 encodes heat shock protein 40 (HSP40), a molecular chaperone. Knocking down Dnajc3 in the high regenerative strain (BXD90) led to a decreased regeneration response, whereas, overexpression of Dnajc3 in a low regenerative strain (BXD34) resulted in an increased regeneration response. These findings reveal that Dnajc3 not only increases the number of regenerating axons, but also increases the distance that axons travel. The enhanced regeneration will prove to be critical for functional recovery in humans, where the distance axons travel to their targets is considerably longer than that of mice.

Key words: axon regeneration, complex trait, Dnajc3, genomics, heat shock protein 40, mouse, optic nerve, retinal ganglion cell