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RBM5 Is a Male Germ Cell Splicing Factor and Is Required for Spermatid Differentiation and Male Fertility.
MedLine Citation:
PMID:  23935508     Owner:  NLM     Status:  In-Data-Review    
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 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.
Moira K O'Bryan; Brett J Clark; Eileen A McLaughlin; Rebecca J D'Sylva; Liza O'Donnell; Jacqueline A Wilce; Jessie Sutherland; Anne E O'Connor; Belinda Whittle; Christopher C Goodnow; Christopher J Ormandy; Duangporn Jamsai
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Publication Detail:
Type:  Journal Article     Date:  2013-07-25
Journal Detail:
Title:  PLoS genetics     Volume:  9     ISSN:  1553-7404     ISO Abbreviation:  PLoS Genet.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-08-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101239074     Medline TA:  PLoS Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e1003628     Citation Subset:  IM    
Department of Anatomy & Developmental Biology, Monash University, Melbourne, Australia ; The ARC Centre of Excellence in Biotechnology & Development, Monash University, Melbourne, Australia.
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