Xu Xiaofeng, Fang Minxi, Chen Lixia, Huang Hao, Dai Zhong-Min, Yang Junlin, Qiu Mengsheng
Zhejiang Key Laboratory of Organ Development and Regeneration, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 311121, China.
College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
Sci Adv. 2024 Dec 13;10(50):eadf8405. doi: 10.1126/sciadv.adf8405.
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. 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 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.
脊椎动物中枢神经系统正常的轴突髓鞘形成和功能在很大程度上依赖于少突胶质细胞（OLs）的及时分化，然而关键的调控因子仍然不明。我们的研究揭示神经锌指蛋白（Nzf2）是一个关键的协调因子，它在发育和髓鞘修复过程中控制OL分化的时机，这与其先前在直接调控髓鞘基因方面所暗示的作用形成对比。敲除Nzf2会延迟OL分化的起始，而过度激活则在发育和髓鞘再生过程中刺激OL分化。利用RNA测序和染色质免疫沉淀测序，我们确定Nkx2.2是Nzf2的一个关键下游靶点。Nzf2在该基因位点的特异性结合通过破坏HDAC1抑制复合物并降低脱乙酰酶活性来抑制组蛋白去乙酰化。此外，Nzf2克服抑制性Notch信号以启动OL分化。因此，我们提出Notch-Nzf2-Nkx2.2轴是OL分化时机机制的一个重要组成部分，这表明Nzf2作为刺激OL分化和促进脱髓鞘疾病中髓鞘修复的潜在治疗靶点。
