EMBO J.: auth.: group Roignant

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