Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (9): 4358-4366.doi: 10.4103/NRR.NRR-D-24-00043

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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).

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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