Ythdf is a N6‐methyladenosine reader that modulates Fmr1 target mRNA selection and restricts axonal growth in Drosophila

Abstract

N6‐methyladenosine (m6A) regulates a variety of physiological processes through modulation of RNA metabolism. This modification is particularly enriched in the nervous system of several species, and its dysregulation has been associated with neurodevelopmental defects and neural dysfunctions. In Drosophila, loss of m6A alters fly behavior, albeit the underlying molecular mechanism and the role of m6A during nervous system development have remained elusive. Here we find that impairment of the m6A pathway leads to axonal overgrowth and misguidance at larval neuromuscular junctions as well as in the adult mushroom bodies. We identify Ythdf as the main m6A reader in the nervous system, being required to limit axonal growth. Mechanistically, we show that the m6A reader Ythdf directly interacts with Fmr1, the fly homolog of Fragile X mental retardation RNA binding protein (FMRP), to inhibit the translation of key transcripts involved in axonal growth regulation. Altogether, this study demonstrates that the m6A pathway controls development of the nervous system and modulates Fmr1 target transcript selection.

Profiling ofN6-methyladenosine dynamics indicates regulation of oyster development by m6A-RNA epitranscriptomes

“…In contrast to cluster 1, their m 6 A pattern is dynamic and shifts from bimodal profiles in early stages to a late mostly unimodal m 6 A distribution around the stop codon. Such 5'-enriched m 6 A profiles are observed in plants (Luo et al 2014), Xenopus (Sai et al 2020), mice (Chang et al 2017) and fruit flies (Worpenberg et al 2021) and may be associated to increased RNA turnover and fast transcript processing depending on the positioning of methylation in the CDS or 5'UTR. Consistently, in developing oysters, the early bimodal m 6 A distribution is associated with a low transcript abundance.…”

“…However, despite the developmental significance of m 6 A is conserved across evolution, several differences exist between animal groups. Indeed, in the fruit fly, m 6 A is mostly present in the 5'UTR of mRNAs throughout head and embryo development (Kan et al 2017;Worpenberg et al 2021), whereas methylation enrichment at 5'UTRs promotes cap-independent translation for transcript selection during the stress response in Vertebrates Meyer et al 2015;Coots et al 2017). In the silkworm Bombyx mori, mRNA is mostly m 6 A-methylated in coding sequences (CDS) but not UTRs, and a high methylation is associated with a high gene expression .…”

Functional Characterization of the m 6 A-Dependent Translational Modulator PfYTH.2 in the Human Malaria Parasite

“…In addition, several other KH domain-containing proteins, including the fragile X mental retardation protein (FMRP), have been identified in mammalian m 6 A interactome screens as putative m 6 A readers (24,25). However, while it is possible that the KH domain is an evolutionarily conserved m 6 A-binding moiety, it is similarly possible that PfKH.1 is a PfYTH.1-interacting protein, as recently reported in Drosophila melanogaster (26), and thus appears as enriched in the oligonucleotide pulldown experiment.…”

Cross‐Talk between Oxidative Stress and m6A RNA Methylation in Cancer

“…The FMRP Translational Regulator 1 (FMR1) and Leucine-Rich Pentatricopeptide Repeat-Containing (LRPPRC) proteins can also read m 6 A modifications and affect RNA behavior [48,49]. Recent studies have reported that FMR1 directly interacts with YTHDF1 to inhibit the translation of target transcripts [50].…”