Two mouse piwi-related genes: miwi and mili

Kuramochi‐Miyagawa, Satomi; Kimura, Tohru; Yomogida, Kentaro; Kuroiwa, Asato; Tadokoro, Yuko; Fujita, Yukiko; Sato, Mototaka; Matsuda, Yoichi; Nakano, Toru

doi:10.1016/s0925-4773(01)00499-3

Cited by 249 publications

(188 citation statements)

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“…Although Miwi2 is expressed from embryonic day 15.5 (E15.5) to the early postnatal period, Miwi is only expressed during the pachytene stage after postnatal day 14, and this expression persists in adult testes (20). On the other hand, Mili is expressed throughout, from germ cells at E12.5 through postnatal to the adult stages of testes development (1,21,22). The fact that Mili is associated with all three developmental stage-dependent pools of piRNAs, prenatal, prepachytene, and pachytene piRNAs, suggests that Mili plays a central role in the piRNA pathway.…”

Section: Resultsmentioning

confidence: 99%

Roles for small noncoding RNAs in silencing of retrotransposons in the mammalian brain

Nandi

Chandramohan

Fioriti

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Piwi-interacting RNAs (piRNAs), long thought to be restricted to germline, have recently been discovered in neurons of Aplysia, with a role in the epigenetic regulation of gene expression underlying long-term memory. We here ask whether piwi/piRNAs are also expressed and have functional roles in the mammalian brain. Large-scale RNA sequencing and subsequent analysis of protein expression revealed the presence in brain of several piRNA biogenesis factors including a mouse piwi (Mili), as well as small RNAs, albeit at low levels, resembling conserved piRNAs in mouse testes [primarily LINE1 (long interspersed nuclear element1) retrotransposon-derived]. Despite the seeming low expression of these putative piRNAs, single-base pair CpG methylation analyses across the genome of Mili/piRNA-deficient (Mili −/− ) mice demonstrate that brain genomic DNA is preferentially hypomethylated within intergenic areas and LINE1 promoter areas of the genome. Furthermore, Mili mutant mice exhibit behavioral deficits such as hyperactivity and reduced anxiety. These results suggest that putative piRNAs exist in mammalian brain, and similar to the role of piRNAs in testes, they may be involved in the silencing of retrotransposons, which in brain have critical roles in contributing to genomic heterogeneity underlying adaptation, stress response, and brain pathology. We also describe the presence of another class of small RNAs in the brain, with features of endogenous siRNAs, which may have taken over the role of invertebrate piRNAs in their capacity to target both transposons, as well as protein-coding genes. Thus, RNA interference through gene and retrotransposon silencing previously encountered in Aplysia may also have potential roles in the mammalian brain.piwi-interacting RNA | transposon | DNA methylation | behavior | endogenous siRNA P iwi-interacting RNAs (piRNAs) are 26-to 32-nt small noncoding RNAs that associate with the piwi clade of the Argonaute family of proteins and whose primary functions in mammals are associated with the silencing of transposons in the germline through de novo DNA methylation (1-4). Transposons constitute 44% of the human genome and could when active contribute to genetic heterogeneity, to alteration of behavior during adaptation, and to responses to stress. Somatic retrotransposition and its associated insertional mutagenesis have particularly important implications for brain disorders and are often associated with schizophrenia, Rett syndrome, and neurodegenerative disorders (5-7). The LINE1 (long interspersed nuclear element1) family of retrotransposons in particular is active in human and mouse hippocampus (8, 9).Although it has long been thought that piRNA expression and function are restricted to the germline, our laboratory and others have previously found that the piRNA pathway is functional in invertebrate neurons as well (10, 11). Aplysia neurons, in particular, have a strikingly abundant expression of piRNAs (contributing to at least 5% of the total noncoding RNA population); they in turn hav...

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Section: Resultsmentioning

confidence: 99%

Roles for small noncoding RNAs in silencing of retrotransposons in the mammalian brain

Nandi

Chandramohan

Fioriti

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The finding of pi-like tel-sRNAs in mouse somatic cells raises the question whether the Piwi-related slicer activity is present in cells other than male germ line cells. Expression of MILI in prenatal ovaries was reported (Kuramochi-Miyagawa et al 2001), suggesting that not all Piwis in mice are exclusively expressed in the male germ line. Further characterization of the Piwi-family proteins in mammals will help to understand the biogenesis of tel-sRNAs.…”

Section: Resultsmentioning

confidence: 99%

Dicer independent small RNAs associate with telomeric heterochromatin

Cao¹,

Li²,

Hiew³

et al. 2009

RNA

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Small RNAs play important roles in the establishment and maintenance of heterochromatin structures. We show the presence of telomere specific small RNAs (tel-sRNAs) in mouse embryonic stem cells that are ;24 nucleotides in length, Dicer-independent, and 29-O-methylated at the 39 terminus. The tel-sRNAs are asymmetric with specificity toward telomere G-rich strand, and evolutionarily conserved from protozoan to mammalian cells. Furthermore, tel-sRNAs are up-regulated in cells that carry null mutation of H3K4 methyltransferase MLL (Mll (À/À) ) and down-regulated in cells that carry null mutations of histone H3K9 methyltransferase SUV39H (Suv39h1/h2 (À/À) ), suggesting that they are subject to epigenetic regulation. These results support that tel-sRNAs are heterochromatin associated pi-like small RNAs.

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“…They are derived from retrotransposon-rich regions and loaded onto either of the two PIWI proteins, PIWIL2 (also known as MILI) or PIWIL4 (MIWI2) (Kuramochi-Miyagawa et al 2001;Kuramochi-Miyagawa et al 2004;Carmell et al 2007;Aravin et al 2008). Targeted disruptions of the two genes resulted in decreased DNA methylation in retrotransposon sequences and increased levels of their RNAs (Aravin et al 2007b(Aravin et al , 2008Kuramochi-Miyagawa et al 2008).…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

“…In postnatal testes, meiotic spermatocytes and round spermatids express piRNAs of 25-32 nt in length, which are called pachytene piRNAs (Aravin et al 2006;Girard et al 2006;Grivna et al 2006a;Lau et al 2006;Watanabe et al 2006). They interact with PIWIL2 or PIWIL1 (MIWI) (Kuramochi-Miyagawa et al 2001;Deng and Lin 2002) and have diverse sequences that are mapped in clusters in unannotated regions. PIWIL1 is localized to perinuclear structures called chromatoid bodies (Grivna et al 2006b;Kotaja et al 2006;Aravin et al 2009;Chuma et al 2009), which are the presumed sites of PTGS, analogous to the processing bodies in somatic cells (Liu et al 2005).…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

Targeted gene silencing in mouse germ cells by insertion of a homologous DNA into a piRNA generating locus

et al. 2012

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In germ cells, early embryos, and stem cells of animals, PIWI-interacting RNAs (piRNAs) have an important role in silencing retrotransposons, which are vicious genomic parasites, through transcriptional and post-transcriptional mechanisms. To examine whether the piRNA pathway can be used to silence genes of interest in germ cells, we have generated knock-in mice in which a foreign DNA fragment was inserted into a region generating pachytene piRNAs. The knock-in sequence was transcribed, and the resulting RNA was processed to yield piRNAs in postnatal testes. When reporter genes possessing a sequence complementary to portions of the knock-in sequence were introduced, they were greatly repressed after the time of pachytene piRNA generation. This repression mainly occurred at the post-transcriptional level, as degradation of the reporter RNAs was accelerated. Our results show that the piRNA pathway can be used as a tool for sequence-specific gene silencing in germ cells and support the idea that the piRNA generating regions serve as traps for retrotransposons, enabling the host cell to generate piRNAs against active retrotransposons.

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Two mouse piwi-related genes: miwi and mili

Cited by 249 publications

References 27 publications

Roles for small noncoding RNAs in silencing of retrotransposons in the mammalian brain

Roles for small noncoding RNAs in silencing of retrotransposons in the mammalian brain

Dicer independent small RNAs associate with telomeric heterochromatin

Targeted gene silencing in mouse germ cells by insertion of a homologous DNA into a piRNA generating locus

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