Essential Role for endogenous siRNAs during meiosis in mouse oocytes.

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Stein, Paula 
Rozhkov, Nikolay V 
Li, Fan 
Cárdenas, Fabián L 
Davydenko, Olga 

The RNase III enzyme DICER generates both microRNAs (miRNAs) and endogenous short interfering RNAs (endo-siRNAs). Both small RNA species silence gene expression post-transcriptionally in association with the ARGONAUTE (AGO) family of proteins. In mammals, there are four AGO proteins (AGO1-4), of which only AGO2 possesses endonucleolytic activity. siRNAs trigger endonucleolytic cleavage of target mRNAs, mediated by AGO2, whereas miRNAs cause translational repression and mRNA decay through association with any of the four AGO proteins. Dicer deletion in mouse oocytes leads to female infertility due to defects during meiosis I. Because mouse oocytes express both miRNAs and endo-siRNAs, this phenotype could be due to the absence of either class of small RNA, or both. However, we and others demonstrated that miRNA function is suppressed in mouse oocytes, which suggested that endo-siRNAs, not miRNAs, are essential for female meiosis. To determine if this was the case we generated mice that express a catalytically inactive knock-in allele of Ago2 (Ago2ADH) exclusively in oocytes and thereby disrupted the function of siRNAs. Oogenesis and hormonal response are normal in Ago2ADH oocytes, but meiotic maturation is impaired, with severe defects in spindle formation and chromosome alignment that lead to meiotic catastrophe. The transcriptome of these oocytes is widely perturbed and shows a highly significant correlation with the transcriptome of Dicer null and Ago2 null oocytes. Expression of the mouse transcript (MT), the most abundant transposable element in mouse oocytes, is increased. This study reveals that endo-siRNAs are essential during meiosis I in mouse females, demonstrating a role for endo-siRNAs in mammals.

Animals, Argonaute Proteins, DNA Transposable Elements, Embryonic Stem Cells, Female, Gene Expression Profiling, Gene Expression Regulation, Developmental, Germ Cells, Infertility, Female, Meiosis, Mice, MicroRNAs, Oocytes, RNA, Small Interfering
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PLoS Genet
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Public Library of Science (PLoS)
This research was supported by the National Institutes of Health Grants HD022681 (to RMS), and R37 GM062534-14 (to GJH), National Human Genome Research Institute 5T32HG000046-13 (to FL) and by a kind gift from Kathryn W. Davis. GJH is an investigator of the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.