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Haussmann, I.U., Bodi, Z., Sanchez-Moran, E., Mongan, N.P., Archer, N., Fray, R.G., Soller, M. (2016). m(6)A potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination.  Nature 540(7632): 301--304.
FlyBase ID
FBrf0234210
Publication Type
Research paper
Abstract

N(6)-methyladenosine (m(6)A) is the most common internal modification of eukaryotic messenger RNA (mRNA) and is decoded by YTH domain proteins. The mammalian mRNA m(6)A methylosome is a complex of nuclear proteins that includes METTL3 (methyltransferase-like 3), METTL14, WTAP (Wilms tumour 1-associated protein) and KIAA1429. Drosophila has corresponding homologues named Ime4 and KAR4 (Inducer of meiosis 4 and Karyogamy protein 4), and Female-lethal (2)d (Fl(2)d) and Virilizer (Vir). In Drosophila, fl(2)d and vir are required for sex-dependent regulation of alternative splicing of the sex determination factor Sex lethal (Sxl). However, the functions of m(6)A in introns in the regulation of alternative splicing remain uncertain. Here we show that m(6)A is absent in the mRNA of Drosophila lacking Ime4. In contrast to mouse and plant knockout models, Drosophila Ime4-null mutants remain viable, though flightless, and show a sex bias towards maleness. This is because m(6)A is required for female-specific alternative splicing of Sxl, which determines female physiognomy, but also translationally represses male-specific lethal 2 (msl-2) to prevent dosage compensation in females. We further show that the m(6)A reader protein YT521-B decodes m(6)A in the sex-specifically spliced intron of Sxl, as its absence phenocopies Ime4 mutants. Loss of m(6)A also affects alternative splicing of additional genes, predominantly in the 5' untranslated region, and has global effects on the expression of metabolic genes. The requirement of m(6)A and its reader YT521-B for female-specific Sxl alternative splicing reveals that this hitherto enigmatic mRNA modification constitutes an ancient and specific mechanism to adjust levels of gene expression.

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Related Publication(s)
Personal communication to FlyBase

Location data for the Ime4[Delta22-3] deletion.
Soller and Song, 2017.2.17, Location data for the Ime4[Delta22-3] deletion. [FBrf0234863]

Gene nomenclature for m6A pathway components.
Lai et al., 2017.8.30, Gene nomenclature for m6A pathway components. [FBrf0236550]

Mettl3 and Ythdc1 constructs and insertions.
Soller, 2018.2.14, Mettl3 and Ythdc1 constructs and insertions. [FBrf0238213]

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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Nature
    Title
    Nature
    Publication Year
    1869-
    ISBN/ISSN
    0028-0836
    Data From Reference
    Aberrations (3)
    Alleles (11)
    Gene Groups (2)
    Genes (17)
    Physical Interactions (2)
    Cell Lines (1)
    Natural transposons (1)
    Insertions (7)
    Experimental Tools (2)
    Transgenic Constructs (4)