Li Qingfeng, Liu Hui, Li Lishi, Guo Haomin, Xie Zhihao, Kong Xuejian, Xu Jiamin, Zhang Junlin, Chen Yunxia, Zhang Zhongsheng, Liu Jun, Xuan Aiguo
The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China.
School of Basic Medical Sciences, First Clinical School, School of Health Management, Guangzhou Medical University, Guangzhou, 511436, China.
Cell Biosci. 2023 Oct 1;13(1):183. doi: 10.1186/s13578-023-01131-2.
N-methylguanosine (mG) is one of the most conserved modifications in nucleosides impacting mRNA export, splicing, and translation. However, the precise function and molecular mechanism of internal mRNA mG methylation in adult hippocampal neurogenesis and neurogenesis-related Alzheimer's disease (AD) remain unknown.
We profiled the dynamic Mettl1/Wdr4 expressions and mG modification during neuronal differentiation of neural stem cells (NSCs) in vitro and in vivo. Adult hippocampal neurogenesis and its molecular mechanisms were examined by morphology, biochemical methods and biological sequencing. The translation efficiency of mRNA was detected by polysome profiling. The stability of Sptbn2 mRNA was constructed by RNA stability assay. APPswe/PS1ΔE9 (APP/PS1) double transgenic mice were used as model of AD. Morris water maze was used to detect the cognitive function.
We found that mG methyltransferase complex Mettl1/Wdr4 as well as mG was significantly elevated in neurons. Functionally, silencing Mettl1 in neural stem cells (NSCs) markedly decreased mG modification, neuronal genesis and proliferation in addition to increasing gliogenesis, while forced expression of Mettl1 facilitated neuronal differentiation and proliferation. Mechanistically, the mG modification of Sptbn2 mRNA by Mettl1 enhanced its stability and translation, which promoted neurogenesis. Importantly, genetic defciency of Mettl1 reduced hippocampal neurogenesis and spatial memory in the adult mice. Furthermore, Mettl1 overexpression in the hippocampus of APP/PS1 mice rescued neurogenesis and behavioral defects.
Our findings unravel the pivotal role of internal mRNA mG modification in Sptbn2-mediated neurogenesis, and highlight Mettl3 regulation of neurogenesis as a novel therapeutic target in AD treatment.
N-甲基鸟苷（mG）是核苷中最保守的修饰之一，影响mRNA输出、剪接和翻译。然而，成年海马神经发生及与神经发生相关的阿尔茨海默病（AD）中内部mRNA mG甲基化的确切功能和分子机制仍不清楚。
我们分析了体外和体内神经干细胞（NSCs）神经元分化过程中Mettl1/Wdr4的动态表达和mG修饰。通过形态学、生化方法和生物测序研究成年海马神经发生及其分子机制。通过多核糖体谱分析检测mRNA的翻译效率。通过RNA稳定性测定构建Sptbn2 mRNA的稳定性。APPswe/PS1ΔE9（APP/PS1）双转基因小鼠用作AD模型。采用莫里斯水迷宫检测认知功能。
我们发现mG甲基转移酶复合物Mettl1/Wdr4以及mG在神经元中显著升高。在功能上，沉默神经干细胞（NSCs）中的Mettl1除了增加神经胶质生成外，还显著降低mG修饰、神经元发生和增殖，而强制表达Mettl1则促进神经元分化和增殖。机制上，Mettl1对Sptbn2 mRNA的mG修饰增强了其稳定性和翻译，从而促进神经发生。重要的是，Mettl1基因缺陷降低了成年小鼠的海马神经发生和空间记忆。此外，在APP/PS1小鼠海马中过表达Mettl1可挽救神经发生和行为缺陷。
我们的研究结果揭示了内部mRNA mG修饰在Sptbn2介导的神经发生中的关键作用，并强调Mettl3对神经发生的调节作为AD治疗的新靶点。
