Ythdf is a N6‐methyladenosine reader that modulates Fmr1 target mRNA selection and restricts axonal growth in Drosophila
Open Access
- 11 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 40 (4), e104975
- https://doi.org/10.15252/embj.2020104975
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.Keywords
Funding Information
- Université de Lausanne
- Deutsche Forschungsgemeinschaft (RO 4681/6‐1, RO 4681/9‐1, RO 4681/12‐1, RO 4681/13‐1, 752621)
- European Cooperation in Science and Technology (CA16120)
- KWF Kankerbestrijding
- Horizon 2020 Framework Programme
- Boehringer Ingelheim
This publication has 99 references indexed in Scilit:
- FLEXBAR—Flexible Barcode and Adapter Processing for Next-Generation Sequencing PlatformsBiology, 2012
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop CodonsCell, 2012
- FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and AutismCell, 2011
- Proteomics, Ultrastructure, and Physiology of Hippocampal Synapses in a Fragile X Syndrome Mouse Model Reveal Presynaptic PhenotypeOnline Journal of Public Health Informatics, 2011
- Aging in fragile X syndromeJournal of Neurodevelopmental Disorders, 2010
- Fast and accurate short read alignment with Burrows–Wheeler transformBioinformatics, 2009
- Excess protein synthesis in Drosophila Fragile X mutants impairs long-term memoryNature Neuroscience, 2008
- Deletion of FMR1 in Purkinje Cells Enhances Parallel Fiber LTD, Enlarges Spines, and Attenuates Cerebellar Eyelid Conditioning in Fragile X SyndromeNeuron, 2005
- Influence of stimulants on electrodermal studies in Fragile X syndromeMicroscopy Research and Technique, 2002