EMBO J.: auth.: group Roignant

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EMBO J. 2021 Jan 11;e104975. doi: 10.15252/embj.2020104975. Online ahead of print.

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

Lina Worpenberg 1, Chiara Paolantoni 1, Sara Longhi 2, Miriam M Mulorz 3, Tina Lence 3, Hans-Hermann Wessels 4 5, Erik Dassi 6, Giuseppe Aiello 7, F X Reymond Sutandy 3, Marion Scheibe 3, Raghu R Edupuganti 8, Anke Busch 9, Martin M Möckel 10, Michiel Vermeulen 8, Falk Butter 3, Julian König 3, Michela Notarangelo 2, Uwe Ohler 4 5, Christoph Dieterich 11 12, Alessandro Quattrone 2, Alessia Soldano 2, Jean-Yves Roignant 1 13Affiliations expand

Abstract

N6-methyladenosine (m6 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 m6 A alters fly behavior, albeit the underlying molecular mechanism and the role of m6 A during nervous system development have remained elusive. Here we find that impairment of the m6 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 m6 A reader in the nervous system, being required to limit axonal growth. Mechanistically, we show that the m6 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 m6 A pathway controls development of the nervous system and modulates Fmr1 target transcript selection.