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RBM5 Is a Male Germ Cell Splicing Factor and Is Required for Spermatid Differentiation and Male Fertility

O'Bryan, Moira K; Clark, Brett J; McLaughlin, Eileen A; D'Sylva, Rebecca J; O'Donnell, Liza; Wilce, Jacqueline A; Sutherland, Jessie; O'Connor, Anne E; Whittle, Belinda; Goodnow, Christopher C; Ormandy, Christopher J; Jamsai, Duangporn

Description

Alternative splicing of precursor messenger RNA (pre-mRNA) is common in mammalian cells and enables the production of multiple gene products from a single gene, thus increasing transcriptome and proteome diversity. Disturbance of splicing regulation is associated with many human diseases; however, key splicing factors that control tissue-specific alternative splicing remain largely undefined. In an unbiased genetic screen for essential male fertility genes in the mouse, we identified the RNA...[Show more]

dc.contributor.authorO'Bryan, Moira K
dc.contributor.authorClark, Brett J
dc.contributor.authorMcLaughlin, Eileen A
dc.contributor.authorD'Sylva, Rebecca J
dc.contributor.authorO'Donnell, Liza
dc.contributor.authorWilce, Jacqueline A
dc.contributor.authorSutherland, Jessie
dc.contributor.authorO'Connor, Anne E
dc.contributor.authorWhittle, Belinda
dc.contributor.authorGoodnow, Christopher C
dc.contributor.authorOrmandy, Christopher J
dc.contributor.authorJamsai, Duangporn
dc.date.accessioned2015-11-25T04:09:30Z
dc.date.available2015-11-25T04:09:30Z
dc.identifier.issn1553-7404
dc.identifier.urihttp://hdl.handle.net/1885/16794
dc.description.abstractAlternative splicing of precursor messenger RNA (pre-mRNA) is common in mammalian cells and enables the production of multiple gene products from a single gene, thus increasing transcriptome and proteome diversity. Disturbance of splicing regulation is associated with many human diseases; however, key splicing factors that control tissue-specific alternative splicing remain largely undefined. In an unbiased genetic screen for essential male fertility genes in the mouse, we identified the RNA binding protein RBM5 (RNA binding motif 5) as an essential regulator of haploid male germ cell pre-mRNA splicing and fertility. Mice carrying a missense mutation (R263P) in the second RNA recognition motif (RRM) of RBM5 exhibited spermatid differentiation arrest, germ cell sloughing and apoptosis, which ultimately led to azoospermia (no sperm in the ejaculate) and male sterility. Molecular modelling suggested that the R263P mutation resulted in compromised mRNA binding. Within the adult mouse testis, RBM5 localises to somatic and germ cells including spermatogonia, spermatocytes and round spermatids. Through the use of RNA pull down coupled with microarrays, we identified 11 round spermatid-expressed mRNAs as putative RBM5 targets. Importantly, the R263P mutation affected pre-mRNA splicing and resulted in a shift in the isoform ratios, or the production of novel spliced transcripts, of most targets. Microarray analysis of isolated round spermatids suggests that altered splicing of RBM5 target pre-mRNAs affected expression of genes in several pathways, including those implicated in germ cell adhesion, spermatid head shaping, and acrosome and tail formation. In summary, our findings reveal a critical role for RBM5 as a pre-mRNA splicing regulator in round spermatids and male fertility. Our findings also suggest that the second RRM of RBM5 is pivotal for appropriate pre-mRNA splicing.
dc.description.sponsorshipThis work was supported by grants from the National Health and Medical Research Council (NHMRC) to DJ (#606503); the Australian Research Council (ARC) to MKO and CJO; the New South Wales Cancer Council, Cancer Institute New South Wales, Banque Nationale de Paris-Paribas Australia and New Zealand, RT Hall Trust, and the National Breast Cancer Foundation to CJO. DJ was an NHMRC Peter Doherty Postdoctoral Fellow (#384297). MKO and CJO are NHMRC Senior Research Fellows (#545805, #481310). CCG is an NHMRC Australia Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
dc.publisherPublic Library of Science
dc.rights© 2013 O'Bryan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.sourcePLoS Genetics
dc.source.urihttp://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1003628
dc.subjectalternative splicing
dc.subjectanimals
dc.subjectcell cycle proteins
dc.subjectcell differentiation
dc.subjectdna-binding proteins
dc.subjectgerm cells
dc.subjecthumans
dc.subjectinfertility, male
dc.subjectmale
dc.subjectmice
dc.subjectmodels, molecular
dc.subjectmutation
dc.subjectnucleotide motifs
dc.subjectrna, messenger
dc.subjectrna-binding proteins
dc.subjectspermatids
dc.subjecttumor suppressor proteins
dc.titleRBM5 Is a Male Germ Cell Splicing Factor and Is Required for Spermatid Differentiation and Male Fertility
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume9
dc.date.issued2013-07-25
local.identifier.absfor060400
local.identifier.ariespublicationf5625xPUB3928
local.type.statusPublished Version
local.contributor.affiliationO'Bryan, Moira K, Monash University, Australia
local.contributor.affiliationClark, Brett J., Monash University, Australia
local.contributor.affiliationMcLaughlin, E A, University of Newcastle, Australia
local.contributor.affiliationD'Sylva, Rebecca J, Monash University, Australia
local.contributor.affiliationO'Donnell, Liza, Prince Henry's Institute of Medical Research, Australia
local.contributor.affiliationWilce, Jacqueline, Monash University, Australia
local.contributor.affiliationSutherland, Jessie, University of Newcastle, Australia
local.contributor.affiliationWhittle, Belinda, College of Medicine, Biology and Environment, CMBE John Curtin School of Medical Research, Immunology and Infectious Disease, The Australian National University
local.contributor.affiliationGoodnow, Christopher, College of Medicine, Biology and Environment, CMBE John Curtin School of Medical Research, Immunology and Infectious Disease, The Australian National University
local.contributor.affiliationO'Connor, Anne, Monash University, Australia
local.contributor.affiliationOrmandy, Chris, Garvan Institute of Medical Research, Australia
local.contributor.affiliationJamsai, Duyangporn, Monash University, Australia
dc.relationhttp://purl.org/au-research/grants/nhmrc/606503
dc.relationhttp://purl.org/au-research/grants/nhmrc/384297
dc.relationhttp://purl.org/au-research/grants/nhmrc/545805
dc.relationhttp://purl.org/au-research/grants/nhmrc/481310
local.identifier.essn1553-7404
local.bibliographicCitation.issue7
local.bibliographicCitation.startpagee1003628
local.identifier.doi10.1371/journal.pgen.1003628
dc.date.updated2015-12-11T08:33:03Z
local.identifier.scopusID2-s2.0-84880764141
local.identifier.thomsonID000322321100030
CollectionsANU Research Publications

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