m6A facilitates hippocampus-dependent learning and memory through YTHDF1

Hailing Shi, Xuliang Zhang, Yi-Lan Weng, Zongyang Lu, Yajing Liu, Zhike Lu, Jianan Li, Piliang Hao, Yu Zhang, Feng Zhang, You Wu, Jary Y. Delgado, Yijing Su, Meera J. Patel, Xiaohua Cao, Bin Shen, Xingxu Huang, Guo-li Ming, Xiaoxi Zhuang, Hongjun Song (), Chuan He () and Tao Zhou ()
Additional contact information
Hailing Shi: The University of Chicago
Xuliang Zhang: ShanghaiTech University
Yi-Lan Weng: University of Pennsylvania
Zongyang Lu: ShanghaiTech University
Yajing Liu: ShanghaiTech University
Zhike Lu: The University of Chicago
Jianan Li: ShanghaiTech University
Piliang Hao: ShanghaiTech University
Yu Zhang: ShanghaiTech University
Feng Zhang: University of Pennsylvania
You Wu: Tongji University
Jary Y. Delgado: The University of Chicago
Yijing Su: University of Pennsylvania
Meera J. Patel: The University of Chicago
Xiaohua Cao: Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Sciences, East China Normal University
Bin Shen: Nanjing Medical University
Xingxu Huang: ShanghaiTech University
Guo-li Ming: University of Pennsylvania
Xiaoxi Zhuang: The University of Chicago
Hongjun Song: University of Pennsylvania
Chuan He: The University of Chicago
Tao Zhou: ShanghaiTech University

Nature, 2018, vol. 563, issue 7730, 249-253

Abstract: Abstract N6-methyladenosine (m6A), the most prevalent internal RNA modification on mammalian messenger RNAs, regulates the fates and functions of modified transcripts through m6A-specific binding proteins1–5. In the nervous system, m6A is abundant and modulates various neural functions6–11. Whereas m6A marks groups of mRNAs for coordinated degradation in various physiological processes12–15, the relevance of m6A for mRNA translation in vivo remains largely unknown. Here we show that, through its binding protein YTHDF1, m6A promotes protein translation of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory. Mice with genetic deletion of Ythdf1 show learning and memory defects as well as impaired hippocampal synaptic transmission and long-term potentiation. Re-expression of YTHDF1 in the hippocampus of adult Ythdf1-knockout mice rescues the behavioural and synaptic defects, whereas hippocampus-specific acute knockdown of Ythdf1 or Mettl3, which encodes the catalytic component of the m6A methyltransferase complex, recapitulates the hippocampal deficiency. Transcriptome-wide mapping of YTHDF1-binding sites and m6A sites on hippocampal mRNAs identified key neuronal genes. Nascent protein labelling and tether reporter assays in hippocampal neurons showed that YTHDF1 enhances protein synthesis in a neuronal-stimulus-dependent manner. In summary, YTHDF1 facilitates translation of m6A-methylated neuronal mRNAs in response to neuronal stimulation, and this process contributes to learning and memory.

Keywords: Adult Mouse Hippocampus; Contextual Fear Memory; mM Methyl Methanethiosulfonate (MMTS); PBS With 0.1% Tween-20 (PBST); Protein Synthesis Assay (search for similar items in EconPapers)
Date: 2018
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DOI: 10.1038/s41586-018-0666-1

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