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

## TL;DR

This study shows that a specific RNA modification pathway is crucial for learning and memory in fruit flies.

## Contribution

The study identifies the m6A/Ythdf pathway's role in Drosophila learning and provides detailed molecular and behavioral analyses.

## Key findings

- m6A/Ythdf pathway is essential for associative learning in Drosophila mushroom bodies.
- Mettl3-dependent m6A sites are enriched in 5’ UTRs and linked to translational activation.
- m6A modification does not affect RNA stability but influences translational efficiency.

## 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.

Epitranscriptomic modifications can regulate learning and memory. Here, the authors provide proteomic and functional analysis of N6-methyladenosine (m6A)-binding proteins in D. melanogaster and unveil behavioral and regulatory defects for m6A/Ythdf mutants.