Flores Joana V, Cordero-Espinoza Lucía, Oeztuerk-Winder Feride, Andersson-Rolf Amanda, Selmi Tommaso, Blanco Sandra, Tailor Jignesh, Dietmann Sabine, Frye Michaela
Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK; Wellcome Trust/Cancer Research UK Gurdon Institute, Henry Wellcome Building of Cancer and Developmental Biology, Tennis Court Road, Cambridge CB2 1QN, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
Stem Cell Reports. 2017 Jan 10;8(1):112-124. doi: 10.1016/j.stemcr.2016.11.014. Epub 2016 Dec 29.
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.
胞嘧啶-5 RNA甲基转移酶NSUN2的功能丧失突变会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NSUN2在发育中的人类大脑的早期神经上皮祖细胞中表达，并且在体外人神经上皮干细胞（NES）分化过程中其表达逐渐降低。在发育中的Nsun2小鼠大脑皮层中，中间祖细胞积累，上层神经元减少。NSUN2介导的tRNA甲基化缺失会增加血管生成素对其的核酸内切酶切割，并且5' tRNA片段在Nsun2大脑中积累。NSUN2的缺失和血管生成素的存在均会损害NES细胞的神经分化。由于NSUN2的抑制也会抑制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NSUN2的情况下分化能力受损可能是由于无法有效响应生长因子所致。
