MIWI2 Is Essential for Spermatogenesis and Repression of Transposons in the Mouse Male Germline

Cold Spring Harbor Laboratory, Howard Hughes Medical Institute, Watson School of Biological Sciences, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
Developmental Cell (Impact Factor: 9.71). 04/2007; 12(4):503-14. DOI: 10.1016/j.devcel.2007.03.001
Source: PubMed


Small RNAs associate with Argonaute proteins and serve as sequence-specific guides for regulation of mRNA stability, productive translation, chromatin organization, and genome structure. In animals, the Argonaute superfamily segregates into two clades. The Argonaute clade acts in RNAi and in microRNA-mediated gene regulation in partnership with 21-22 nt RNAs. The Piwi clade, and their 26-30 nt piRNA partners, have yet to be assigned definitive functions. In mice, two Piwi-family members have been demonstrated to have essential roles in spermatogenesis. Here, we examine the effects of disrupting the gene encoding the third family member, MIWI2. Miwi2-deficient mice display a meiotic-progression defect in early prophase of meiosis I and a marked and progressive loss of germ cells with age. These phenotypes may be linked to an inappropriate activation of transposable elements detected in Miwi2 mutants. Our observations suggest a conserved function for Piwi-clade proteins in the control of transposons in the germline.

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Available from: Henk van de Kant, Aug 14, 2014
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    • "Since they maintain genomic stability in the germline, piRNAs are indispensable for fertility[Aravin et al., 2007]. The 3 members of the Piwi protein family in the mouse are required for spermatogenesis[Deng and Lin, 2002;Kuramochi-Miyagawa et al., 2004;Carmell et al., 2007]. Inactivation of Miwi2 (Piwil4) or Mili (Piwil2) leads to loss of DNA methylation, derepression of transposons, defects in spermatogenesis, and sterility [Aravin and Hannon, 2008]. "
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    • "In mouse, the piRNA pathway is required during germline reprogramming for re-establishment of epigenetic silencing and post-transcriptional cleavage of long interspersed elements (LINE-1) and intracisternal A-particle (IAP) sequences (Aravin et al., 2008, 2007; De Fazio et al., 2011; Kuramochi-Miyagawa et al., 2008) and subsequent maintenance of LINE-1 silencing of spermatogonia, meiocytes , and spermatids (Di Giacomo et al., 2013, 2015; Reuter et al., 2011). Deficiency of genes required for piRNA biogenesis (e.g., PIWIL proteins MILI and MIWI2, the phospholipase MITOPLD [a phospholipase D family member], helicase MOV10L1, the piRNA biogenesis factor MAEL, and the Tudor domain protein TDRD9) is characterized by arrest of spermatogenesis and infertility in males (Carmell et al., 2007; Castañ eda et al., 2014; Deng and Lin, 2002; Kuramochi-Miyagawa et al., 2004; Shoji et al., 2009; Vasileva et al., 2009; Watanabe et al., 2011; Zheng and Wang, 2012). In contrast, females with deficiency in these genes remain fertile and without an apparent phenotype. "
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    ABSTRACT: Piwi-interacting RNAs (piRNAs), a class of 26- to 32-nt non-coding RNAs (ncRNAs), function in germline development, transposon silencing, and epigenetic regulation. We performed deep sequencing and annotation of untreated and periodate-treated small RNA cDNA libraries from human fetal and adult germline and reference somatic tissues. This revealed abundant piRNAs originating from 150 piRNA-encoding genes, including some exhibiting gender-specific expression, in fetal ovary and adult testis-developmental periods coinciding with mitotic cell divisions expanding fetal germ cells prior to meiotic divisions. The absence of reads mapping uniquely to annotated piRNA genes demonstrated their paucity in fetal testis and adult ovary and absence in somatic tissues. We curated human piRNA-expressing regions and defined their precise borders and observed piRNA-guided cleavage of transcripts antisense to some piRNA-producing genes. This study provides insights into sex-specific mammalian piRNA expression and function and serves as a reference for human piRNA analysis and annotation.
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    • "The piRNAs are associated with members of the PIWI subfamily of Argonaute proteins; in the mouse there are three PIWI-like proteins: MIWI/ PIWIL1, MILI/PIWIL2 and MIWI2/PIWIL4. MIWI2 and MILI are involved in male meiotic progression and deletion of their genes leads to male sterility (Carmell et al., 2007; Kuramochi-Miyagawa et al., 2004). In addition, piRNAs are also involved in TE silencing at the transcriptional level by the DNA methylation in mammalian germ cells (Bourc'his and Bestor, 2004 and ref in: Castel and Martienssen (2013)). "
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