中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (9): 4358-4366.doi: 10.4103/NRR.NRR-D-24-00043

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

Argonaute 2对微小RNA的稳定化调控成人神经发生与少突胶质细胞生成 

  

  • 出版日期:2026-09-15 发布日期:2026-05-22

Argonaute 2 stabilization of microRNAs controls adult neurogenesis and oligodendrogenesis

Xianshuang Liu1, *, #, Wanlong Pan1, #, †, Michael Chopp1, 2, Baoyan Fan1, Xinli Wang1, Julie Landschoot-Ward1, Min Wei1, Qinge Lu1, Helen Liu1, William Golembieski1, Sutapa Santra1, Zheng Gang Zhang1   

  1. 1Department of Neurology, Henry Ford Hospital, Detroit, MI, USA; 
    2Department of Physics, Oakland University, Rochester, MI, USA
  • Online:2026-09-15 Published:2026-05-22
  • Contact: Xianshuang Liu, PhD, xliu2@hfhs.org.
  • Supported by:
    This work was supported by U.S. National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Diacomp Program grant 21AU4165 (to XL) and American Heart/Stroke Association Grant 18IPA34170331 (to XL).

摘要:

微小RNA调控神经干细胞功能。作为RNA诱导沉默复合体的组成蛋白,Argonaute 2在miRNA介导的转录后基因沉默中发挥关键作用。尽管Argonaute 2与微小RNA被公认为RNA诱导沉默复合体的核心调控因子,其在成年神经干细胞功能中的精确作用尚不明确。特别是,尚不清楚Argonaute 2是否对维持成年脑中神经干细胞的增殖、神经发生和少突胶质细胞生成必不可少,也不清楚其缺失如何影响缺血损伤后的恢复。实验探讨了成年神经干细胞中Argonaute 2缺失对神经发生和少突胶质细胞生成的影响。在Ascl1谱系神经干细胞中实现Argonaute 2条件性诱导性缺失的成年转基因小鼠,其侧脑室-脑室下区及齿状回颗粒下区的神经发生能力均显著降低,表现为神经干细胞增殖与神经母细胞数量减少。Argonaute 2缺失还导致胼胝体少突胶质细胞生成减少,表现为少突胶质细胞前体增殖能力下降及成熟少突胶质细胞数量减少。此外,在缺血小鼠成年神经干细胞中敲除Argonaute 2会加剧感觉运动功能和认知功能障碍。机制上,神经干细胞中Argonaute 2缺失降低了成熟微小RNA的稳定性,下调了参与调控神经干细胞功能的Shh、Notch和转化生长因子β信号通路相关基因。综上,实验证实Argonaute 2对成年神经干细胞介导的神经发生和少突胶质细胞生成至关重要,其缺失会加剧缺血后的功能恢复障碍。通过揭示Argonaute 2稳定成熟微小RNA的作用,该研究揭示了神经干细胞调控的新机制,并指出Argonaute 2可作为神经退行性及缺血性脑疾病的潜在治疗靶点。


https://orcid.org/0000-0003-2414-321X (Xianshuang Liu)

关键词: Argonaute 2lmicroRNAl神经干细胞l神经发生l少突胶质细胞生成l稳定性l脑卒中l脑室下区

Abstract: MicroRNAs regulate neural stem cell function. Argonaute 2 protein, constituent of the RNA-induced silencing complex, plays an important role in regulating microRNA function for post-transcriptional gene silencing. Although Argonaute 2 and microRNAs are recognized as central regulators of RNA-induced silencing complex, their precise role in adult neural stem cell function has remained unclear. In particular, it was not known whether Argonaute 2 is required for sustaining neural stem cell proliferation, neurogenesis, and oligodendrogenesis in the adult brain, or how its loss might influence recovery after ischemic injury. The present study examined the effect of Argonaute 2 deletion in adult neural stem cells on neurogenesis and oligodendrogenesis. Adult transgenic mice with conditional and inducible ablation of Argonaute 2 in Ascl1-lineage neural stem cells exhibited the reduction of neurogenesis in the ventricular–subventricular zone of the lateral ventricle and in the subgranular zone of the dentate gyrus, as evidenced by a decrease in neural stem cell proliferation and neuroblast numbers. Argonaute 2 deletion also reduced oligodendrogenesis in the corpus callosum, as indicated by the reduction of oligodendrocyte progenitor cell proliferation and the number of mature oligodendrocytes. Additionally, deleting Argonaute 2 in adult neural stem cells of ischemic mice exacerbated impairments of sensorimotor and cognitive functions. Mechanistically, Argonaute 2 ablation in neural stem cells reduced the stability of mature microRNAs and downregulated genes involved in the Shh (Sonic Hedgehog), Notch, and TGFβ (transforming growth factor beta) signaling pathways, which regulate the functions of neural stem cells. Collectively, our study demonstrates that Argonaute 2 is essential for adult neural stem cell-mediated neurogenesis and oligodendrogenesis, with its deletion worsening recovery after ischemia. By revealing that Argonaute 2 stabilizes mature microRNAs, our work uncovers a novel mechanism of neural stem cell regulation and highlights Argonaute 2 as a potential therapeutic target for neurodegenerative and ischemic brain diseases.

Key words: Argonaute 2l microRNAl neural stem cellsl neurogenesisl oligodendrogenesisl stabilityl strokel subventricular zone