CMTr cap-adjacent 2′-O-ribose mRNA methyltransferases are required for reward learning and mRNA localization to synapses

Irmgard Haussmann, Yanying Wu, Mohanakarthik Ponnadai Nallasivan, Nathan Archer, Zsuzsanna Bodi, Daniel Hebenstreit, Scott Waddell, Rupert Fray, Matthias Soller

Research output: Contribution to journalArticlepeer-review

Abstract

Cap-adjacent nucleotides of animal, protist and viral mRNAs can be O-methylated at the 2‘ position of the ribose (cOMe). The functions of cOMe in animals, however, remain largely unknown. Here we show that the two cap methyltransferases (CMTr1 and CMTr2) of Drosophila can methylate the ribose of the first nucleotide in mRNA. Double-mutant flies lack cOMe but are viable. Consistent with prominent neuronal expression, they have a reward learning defect that can be rescued by conditional expression in mushroom body neurons before training. Among CMTr targets are cell adhesion and signaling molecules. Many are relevant for learning, and are also targets of Fragile X Mental Retardation Protein (FMRP). Like FMRP, cOMe is required for localization of untranslated mRNAs to synapses and enhances binding of the cap binding complex in the nucleus. Hence, our study reveals a mechanism to co-transcriptionally prime mRNAs by cOMe for localized protein synthesis at synapses.
Original languageEnglish
Article number1209
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - 8 Mar 2022

Bibliographical note

Funding Information:
We thank S. Brogna, C. Samakovlis, B. Suter, J.-Y. Roignant, M. Ramaswami, FlyORF and the Bloomington and Kyoto stock centers for fly lines, S. Brogna, D. Kopytova, P. Lasko and the Developmental Studies Hybridoma Bank for antibodies, S. Brogna for an oligo(dT) probe, the University of Cambridge Department of Genetics Fly Facility for injections, BacPac for DNA clones, E. Zaharieva for help with stainings, D. Balacco and F. Stappers for help with artwork, and B. Muller and R. Michell for comments on the manuscript. MS is funded by the BBSRC (BB/R002932/1) and the Leverhulme Trust, RGF from BBSRC (BB/R001715/1), DH from WISB, a BBSRC/EPSRC Synthetic Biology Research Centre (BB/M017982/1) and BBSRC (BB/L006340/1), and S.W. by a Wellcome Principal Research Fellowship (200846/Z/16/Z) and an ERC Advanced Grant (789274). NA is a Nottingham Research Fellow funded by the University of Nottingham.

Publisher Copyright:
© 2022, The Author(s).

Keywords

  • Animals
  • Fragile X Mental Retardation Protein/genetics
  • Fragile X Syndrome/genetics
  • Methyltransferases/genetics
  • RNA, Messenger/genetics
  • Reward
  • Ribose/metabolism
  • Synapses/metabolism

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