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A neural m6A/Ythdf pathway is required for learning and memory in Drosophila

Author

Listed:
  • Lijuan Kan

    (Sloan-Kettering Institute)

  • Stanislav Ott

    (Duke-NUS Medical School)

  • Brian Joseph

    (Sloan-Kettering Institute
    Memorial Sloan Kettering Cancer Center)

  • Eun Sil Park

    (Sloan-Kettering Institute)

  • Wei Dai

    (Princeton University)

  • Ralph E. Kleiner

    (Princeton University)

  • Adam Claridge-Chang

    (Duke-NUS Medical School
    A*STAR
    National University of Singapore)

  • Eric C. Lai

    (Sloan-Kettering Institute)

Abstract

Epitranscriptomic modifications can impact behavior. Here, we used Drosophila melanogaster to study N6-methyladenosine (m6A), the most abundant modification of mRNA. Proteomic and functional analyses confirm its nuclear (Ythdc1) and cytoplasmic (Ythdf) YTH domain proteins as major m6A binders. Assays of short term memory in m6A mutants reveal neural-autonomous requirements of m6A writers working via Ythdf, but not Ythdc1. Furthermore, m6A/Ythdf operate specifically via the mushroom body, the center for associative learning. We map m6A from wild-type and Mettl3 mutant heads, allowing robust discrimination of Mettl3-dependent m6A sites that are highly enriched in 5’ UTRs. Genomic analyses indicate that Drosophila m6A is preferentially deposited on genes with low translational efficiency and that m6A does not affect RNA stability. Nevertheless, functional tests indicate a role for m6A/Ythdf in translational activation. Altogether, our molecular genetic analyses and tissue-specific m6A maps reveal selective behavioral and regulatory defects for the Drosophila Mettl3/Ythdf pathway.

Suggested Citation

  • Lijuan Kan & Stanislav Ott & Brian Joseph & Eun Sil Park & Wei Dai & Ralph E. Kleiner & Adam Claridge-Chang & Eric C. Lai, 2021. "A neural m6A/Ythdf pathway is required for learning and memory in Drosophila," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21537-1
    DOI: 10.1038/s41467-021-21537-1
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    Cited by:

    1. Alexandra E. Perlegos & Emily J. Shields & Hui Shen & Kathy Fange Liu & Nancy M. Bonini, 2022. "Mettl3-dependent m6A modification attenuates the brain stress response in Drosophila," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Stanislav Ott & Sangyu Xu & Nicole Lee & Ivan Hong & Jonathan Anns & Danesha Devini Suresh & Zhiyi Zhang & Xianyuan Zhang & Raihanah Harion & Weiying Ye & Vaishnavi Chandramouli & Suresh Jesuthasan & , 2024. "Kalium channelrhodopsins effectively inhibit neurons," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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