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

doi:10.1038/s41467-022-28549-5

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

Biosciences

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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 language	English
Article number	1209
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-28549-5
Publication status	Published - 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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10.1038/s41467-022-28549-5Licence: Creative Commons: Attribution (CC BY)

HaussmannIU2022CMTrFinal published version, 2.96 MBLicence: Creative Commons: Attribution (CC BY)

m6A mRNA methylation - understanding an essential mechanism adjusting gene expression during development and differentiation
Soller, M.
Biotechnology & Biological Sciences Research Council
6/08/18 → 7/02/23
Project: Research Councils

Cite this

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

abstract = "Cap-adjacent nucleotides of animal, protist and viral mRNAs can be O-methylated at the 2{\textquoteleft} 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.",

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author = "Irmgard Haussmann and Yanying Wu and {Ponnadai Nallasivan}, Mohanakarthik and Nathan Archer and Zsuzsanna Bodi and Daniel Hebenstreit and Scott Waddell and Rupert Fray and Matthias Soller",

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: {\textcopyright} 2022, The Author(s).",

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AU - Haussmann, Irmgard

AU - Wu, Yanying

AU - Ponnadai Nallasivan, Mohanakarthik

AU - Archer, Nathan

AU - Bodi, Zsuzsanna

AU - Hebenstreit, Daniel

AU - Waddell, Scott

AU - Fray, Rupert

AU - Soller, Matthias

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Y1 - 2022/3/8

N2 - 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.

AB - 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.

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KW - Fragile X Syndrome/genetics

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KW - Synapses/metabolism

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DO - 10.1038/s41467-022-28549-5

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JO - Nature Communications

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ER -

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

Abstract

Bibliographical note

Keywords

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m6A mRNA methylation - understanding an essential mechanism adjusting gene expression during development and differentiation

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