Proper axonal myelination and function of the vertebrate central nervous system rely largely on the timely differentiation of oligodendrocytes (OLs), yet key regulatory factors remain enigmatic. Our study reveals neural zinc finger (Nzf2) as a crucial orchestrator that controls the timing of OL differentiation both during development and myelin repair, contrasting with its previously suggested role in direct myelin gene regulation. Nzf2 ablation delays the onset of OL differentiation, while hyperactivation stimulates OL differentiation both during development and remyelination. Using RNA-seq and ChIP-seq, we pinpoint Nkx2.2 as a critical downstream target of Nzf2. Specific binding of Nzf2 in the Nkx2.2 gene locus inhibits histone deacetylation by disrupting the HDAC1 repressor complex and reducing deacetylase activity. Furthermore, Nzf2 overrides the inhibitory Notch signaling to initiate OL differentiation. Thus, we propose that the Notch-Nzf2-Nkx2.2 axis is a vital component of OL differentiation timing mechanism, suggesting Nzf2 as a potential therapeutic target for stimulating OL differentiation and boosting myelin repair in demyelinating diseases.

中文翻译：

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Nzf2 通过抑制 HDAC1 介导的组蛋白脱乙酰化促进少突胶质细胞分化和再生


脊椎动物中枢神经系统的适当轴突髓鞘形成和功能在很大程度上取决于少突胶质细胞 （OL） 的及时分化，但关键调节因素仍然是个谜。我们的研究揭示了神经锌指 （Nzf2） 是控制发育和髓鞘修复过程中 OL 分化时间的关键协调器，这与之前提出的在直接髓鞘基因调控中的作用形成鲜明对比。Nzf2 消融延迟了 OL 分化的开始，而过度激活在发育和髓鞘再生过程中刺激了 OL 分化。使用 RNA-seq 和 ChIP-seq，我们将 Nkx2.2 确定为 Nzf2 的关键下游靶标。Nzf2 在 Nkx2.2 基因位点中的特异性结合通过破坏 HDAC1 阻遏蛋白复合物和降低脱乙酰酶活性来抑制组蛋白脱乙酰化。此外，Nzf2 覆盖抑制性 Notch 信号传导以启动 OL 分化。因此，我们提出 Notch-Nzf2-Nkx2.2 轴是 OL 分化时序机制的重要组成部分，表明 Nzf2 是刺激 OL 分化和促进脱髓鞘疾病髓鞘修复的潜在治疗靶点。