Dynamic effects of Fto in regulating the proliferation and differentiation of adult neural stem cells of mice
Dynamic effects of Fto in regulating the proliferation and differentiation of adult neural stem cells of mice
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Fto调节小鼠成体神经干细胞增殖和分化的动态作用
DOI：
10.1093/hmg/ddz274
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发表时间：
2020-03-01
影响因子：
3.5
通讯作者：
Li, Xuekun
中科院分区：
文献类型：
--
作者：
Cao, Yuhang;Zhuang, Yingliang;Li, Xuekun
核糖核酸的N-6-甲基腺苷(m(6)A)修饰是由METTL3和Mettl14组成的甲基转移酶复合体沉积的，并被去甲基酶FTO和Alkbh5清除，参与了多种生物学过程。然而，FTO在成体神经干细胞(ANSCs)调控中的具体功能和机制目前仍不清楚。在本研究中，利用条件性基因敲除(CKO)小鼠模型，我们发现在体外和体内，特异性的FTO消融aNSCs可以短暂地增加aNSCs的增殖和促进神经元的分化，但从长期来看，FTO的特异性消融抑制了成年神经发生和神经元的发育。机制上，FTO缺乏导致PDGFRA和SOCS5中m6A修饰显著增加。PDGFRA的高表达和SOCS5的低表达协同促进STAT3的磷酸化。PDGFRA和SOCS5的调节可以修复FTO耗竭所致的神经源性缺陷。我们的结果共同揭示了FTO通过调节PDGFRA/SOCS5-STAT3通路来调节aNSCs的重要作用。
N-6-methyladenosine (m(6)A) modification of RNA is deposited by the methyltransferase complex consisting of Mettl3 and Mettl14 and erased by demethylase Fto and Alkbh5 and is involved in diverse biological processes. However, it remains largely unknown the specific function and mechanism of Fto in regulating adult neural stem cells (aNSCs). In the present study, utilizing a conditional knockout (cKO) mouse model, we show that the specific ablation of Fto in aNSCs transiently increases the proliferation of aNSCs and promotes neuronal differentiation both in vitro and in vivo, but in a long term, the specific ablation of Fto inhibits adult neurogenesis and neuronal development. Mechanistically, Fto deficiency results in a significant increase in m6A modification in Pdgfra and Socs5. The increased expression of Pdgfra and decreased expression of Socs5 synergistically promote the phosphorylation of Stat3. The modulation of Pdgfra and Socs5 can rescue the neurogenic deficits induced by Fto depletion. Our results together reveal an important function of Fto in regulating aNSCs through modulating Pdgfra/Socs5-Stat3 pathway.