Ythdf is a N6‐methyladenosine reader that modulates Fmr1 target mRNA selection and restricts axonal growth in Drosophila. (11th January 2021)

• Record Type: Journal Article
• Authors: Worpenberg, Lina; Paolantoni, Chiara; Longhi, Sara; Mulorz, Miriam M; Lence, Tina; Wessels, Hans‐Hermann; Dassi, Erik; Aiello, Giuseppe; Sutandy, F X Reymond; Scheibe, Marion; Edupuganti, Raghu R; Busch, Anke; Möckel, Martin M; Vermeulen, Michiel; Butter, Falk; König, Julian; Notarangelo, Michela; Ohler, Uwe; Dieterich, Christoph; Quattrone, Alessandro; Soldano, Alessia; Roignant, Jean‐Yves
• Is Part Of: EMBO journal. Volume 40:Number 4(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-01-11
• Subjects: Fmr1 -- m6A -- nervous system -- RNA modification -- Ythdf; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2020104975
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: N6‐methyladenosine (m 6 A) 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 m 6 A alters fly behavior, albeit the underlying molecular mechanism and the role of m 6 A during nervous system development have remained elusive. Here we find that impairment of the m 6 A 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 m 6 A reader in the nervous system, being required to limit axonal growth. Mechanistically, we show that the m 6 A 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 m 6 A pathway controls development of the nervous system and modulates Fmr1 target transcript selection. SYNOPSIS: The m 6 A RNA modification is enriched in the nervous system and its loss or dysregulation is known to affect neuronal development and function through incompletely understood mechanisms. Here, the Drosophila Ythdf is found as an m 6 A reader repressing translation of key neuronal targets of the fly Fragile X mental retardation RNA binding protein Fmr1, thereby modulating axonal growth. Loss‐of‐function mutants of N6‐methyltransferase Mettl3, Ythdf, or Fmr1, exhibit axonal overgrowth at the larval neuromuscular junction (NMJ) and in mushroom bodies (MB). Ythdf and Fmr1 are m 6 A reader proteins with different specificities, binding a common subset of m 6 A‐modified transcripts. Ythdf physically and genetically interacts with Fmr1, and recruits Fmr1 to certain m 6 A‐dependent binding sites. Ythdf and Fmr1 influence translation of specific targets in an m 6 A‐dependent manner. Abstract : Proper neuromuscular junction formation in flies depends on a key mRNA modification guiding translational repression by the Fragile X mental retardation (FMRP) RNA‐binding protein.