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

TitleA neural mA/Ythdf pathway is required for learning and memory in Drosophila.
Publication TypeJournal Article
Year of Publication2021
AuthorsKan, L, Ott, S, Joseph, B, Park, ESil, Dai, W, Kleiner, RE, Claridge-Chang, A, Lai, EC
JournalNat Commun
Volume12
Issue1
Pagination1458
Date Published2021 03 05
ISSN2041-1723
Keywords5' Untranslated Regions, Adenosine, Animals, Drosophila melanogaster, Drosophila Proteins, Female, Learning, Memory, Nuclear Proteins, Proteomics, RNA Stability, RNA, Messenger
Abstract

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

DOI10.1038/s41467-021-21537-1
Alternate JournalNat Commun
PubMed ID33674589
PubMed Central IDPMC7935873
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R01 GM083300 / GM / NIGMS NIH HHS / United States
R01 GM132189 / GM / NIGMS NIH HHS / United States
R01 NS083833 / NS / NINDS NIH HHS / United States