Cytosine-5 RNA Methylation Regulates Neural Stem Cell Differentiation and Motility.
Cytosine-5 RNA Methylation Regulates Neural Stem Cell Differentiation and Motility.
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DOI：
10.1016/j.stemcr.2016.11.014
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发表时间：
2017-01-10
影响因子：
5.9
通讯作者：
Frye M
中科院分区：
文献类型：
--
作者：
Flores JV;Cordero-Espinoza L;Oeztuerk-Winder F;Andersson-Rolf A;Selmi T;Blanco S;Tailor J;Dietmann S;Frye M
胞嘧啶-5 RNA甲基化酶NSUN 2的功能丧失突变导致人类神经发育障碍，但导致包括小头畸形在内的症状的潜在细胞过程仍不清楚。在这里，我们表明，NSUN 2的表达在早期的神经上皮祖细胞的发育中的人脑，其表达逐渐减少在体外分化的人神经上皮干细胞（内斯）。在发育中的Nsun 2 −/−小鼠大脑皮层中，中间祖细胞积累，上层神经元减少。Nsun 2介导的tRNA甲基化的缺失增加了它们被血管生成素的核酸内切切割，5′ tRNA片段在Nsun 2 −/−脑中积累。内斯细胞的神经分化受到NSUN 2缺失和血管生成素存在的损害。由于NSUN 2的抑制也抑制了神经细胞向趋化因子成纤维细胞生长因子2的迁移，我们得出结论，在没有NSUN 2的情况下，受损的分化能力可能是由于无法有效地响应生长因子。NSUN 2标记发育中人脑的早期神经上皮祖细胞NSUN 2的缺失通过减少皮层中的上层神经元导致小头畸形神经上皮干细胞中NSUN 2的缺失损害迁移和分化在这篇文章中，Frye及其同事表明，NSUN 2依赖的RNA甲基化对神经干细胞分化至关重要。缺乏NSUN 2的人神经上皮干细胞对分化和迁移信号的反应延迟。神经干细胞的迁移和分化能力受损可以解释发育中的NSUN 2 −/−小鼠大脑中上层神经元和小头畸形的减少。
Loss-of-function mutations in the cytosine-5 RNA methylase NSUN2 cause neurodevelopmental disorders in humans, yet the underlying cellular processes leading to the symptoms that include microcephaly remain unclear. Here, we show that NSUN2 is expressed in early neuroepithelial progenitors of the developing human brain, and its expression is gradually reduced during differentiation of human neuroepithelial stem (NES) cells in vitro. In the developing Nsun2−/− mouse cerebral cortex, intermediate progenitors accumulate and upper-layer neurons decrease. Loss of NSUN2-mediated methylation of tRNA increases their endonucleolytic cleavage by angiogenin, and 5′ tRNA fragments accumulate in Nsun2−/− brains. Neural differentiation of NES cells is impaired by both NSUN2 depletion and the presence of angiogenin. Since repression of NSUN2 also inhibited neural cell migration toward the chemoattractant fibroblast growth factor 2, we conclude that the impaired differentiation capacity in the absence of NSUN2 may be driven by the inability to efficiently respond to growth factors. NSUN2 marks early neuroepithelial progenitors in the developing human brain Loss of NSUN2 causes microcephaly by reduction of upper-layer neurons in the cortex Loss of NSUN2 in neuroepithelial stem cells impairs migration and differentiation In this article, Frye and colleagues show that NSUN2-dependent RNA methylation is crucial for neural stem cell differentiation. Human neuroepithelial stem cells lacking NSUN2 are delayed in responding to differentiation and migrating cues. The impaired migration and differentiation capacity of neural stem cells may explain the reduction of upper-layer neurons and microcephaly in the developing NSUN2−/− mouse brain.