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

Carmell, Michelle A.; Girard, Angélique; Kant, H. J. G. van de; Bourc’his, Déborah; Bestor, Timothy H.; Rooij, Dirk G. de; Hannon, Gregory J.

doi:10.1016/j.devcel.2007.03.001

Cited by 1,038 publications

(1,058 citation statements)

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“…These prenatal piRNAs are involved not only in PTGS but also in TGS through de novo DNA methylation, because retrotransposons and at least one imprint control region are hypomethylated in Piwil2, Piwil4, and Pld6 (also known as mitoPLD) knockout prospermatogonia (Aravin et al 2007b;Carmell et al 2007;Kuramochi-Miyagawa et al 2008;Watanabe et al 2011). Thus, in the future, it might become possible to introduce epigenetic marks such as DNA methylation to specific genomic regions in germ cells, which could then be inherited by the progeny.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

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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“…For instance, spermatogenesis is arrested at the pachytene spermatocyte stage in Mili-knockout mice [203]. In Miwi2-knockout mice, spermatogenesis stops with meiotic arrest at the leptotene stage [204]. Germ cells in Miwi-deficient mice testis undergo meiosis without elongated spermatids or mature spermatozoa production [205].…”

Section: Mirnas In Spermmentioning

confidence: 99%

A multi-faceted approach to understanding male infertility: gene mutations, molecular defects and assisted reproductive techniques (ART)

Tahmasbpour

Balasubramanian

Agarwal

2014

J Assist Reprod Genet

109

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Background The assisted reproductive techniques aimed to assist infertile couples have their own offspring carry significant risks of passing on molecular defects to next generations. Results Novel breakthroughs in gene and protein interactions have been achieved in the field of male infertility using genome-wide proteomics and transcriptomics technologies. Conclusion Male Infertility is a complex and multifactorial disorder.Significance This review provides a comprehensive, up-todate evaluation of the multifactorial factors involved in male infertility. These factors need to be first assessed and understood before we can successfully treat male infertility.

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“…While MIWI2/Mili is essential for spermatogenesis and repression of transposons in the mouse male germ line, 30 Dnmt3a is an enzyme that catalyzes DNA methylation. 31 While DNA methylation facilitates the inhibitory effect of piRNAs on transposon expression and has important roles in embryonic development, 32 we found that Dnmt3a could methylate the miR-17 promoter, producing a feedforward loop.…”

Section: Discussionmentioning

confidence: 99%

Reciprocal regulation of miRNAs and piRNAs in embryonic development

Yang

Xuan

et al. 2016

Cell Death Differ

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MicroRNAs (miRNAs) and piwi-interacting RNAs (piRNAs) are two classes of small noncoding RNAs, both of which play roles in regulating tissue development. It is unknown whether these distinct classes of noncoding RNAs can regulate one another. Here we show that ectopic expression of miR-17 inhibited mouse fertility and early embryonic development. Specifically, we found that the piRNA amplification loop was repressed by miR-17-5p, leading to increased levels of transposition mutagenesis. This occurred by suppressing the amplification loop of piRNAs with an identical 5′ sequence and by targeting Mili/Miwi2, an essential component of the piRNA amplification loop, and the DNA methyltransferase, Dnmt3a. We also found that increased levels of piRNAs could compete with miRNAs for target binding, resulting in increased expression of Dnmt3a and Mili. Increased Dnmt3a levels could in turn block miR-17-5p expression, while increased Mili expression could accelerate piRNA amplification and inhibit transposon generation, favoring embryonic development. We report for the first time the reciprocal regulation between miRNAs and piRNAs in mouse embryonic development. Cell Death and Differentiation (2016) 23, 1458-1470 doi:10.1038/cdd.2016; published online 18 March 2016A microRNA (miRNA) is a small non-coding RNA molecule of 18-24 nucleotides in length that are post-transcriptional regulators of gene expression. A miRNA has the capacity to affect the stability of hundreds of unique mRNAs 1 and may repress synthesis of hundreds of proteins by base-pairing with the targeting mRNAs. 2 The discovery of miRNAs in gene regulation has improved our understanding of posttranscriptional control of tissue development and aging. 3-5 A polycistronic miRNA cluster, miR-17~92, consisting of six mature miRNAs , and miR-92a-1), has been reported to play a fundamental role in development and remodeling. [6][7][8][9] Furthermore, members of miR-17-92 cluster are found to be commonly down-regulated in aging human cells. 10 We have found that ectopic expression of miR-17 retards tissue growth 11 and inhibits cell senescence. 12 Piwi-interacting RNA (piRNA) is the largest class of small non-coding RNAs expressed by animal cells. 13 piRNAs form complexes with piwi proteins, which function posttranscriptionally in silencing retrotransposons and other genetic elements in germ-line cells. 14 piRNA activity in gene regulation may lead to silencing of transposon expression, 15 as most piRNA sequences are antisense to transposon sequences. 16 The activity of piRNAs in transposon silencing appears to be the most important event during embryonic development. 17 To facilitate silencing transposons in the testes of mammals or in the germ cells of invertebrates, the piwi proteins play essential roles in interacting with piRNAs.These piwi proteins are members of Argonautes, proteins that are needed for gene silencing in miRNA action, including MIWI, MIWI2 and MILI. The sequences of piRNAs guide the piwi proteins to their transposon targets. 17 Decreased expressio...

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

Cited by 1,038 publications

References 55 publications

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

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

A multi-faceted approach to understanding male infertility: gene mutations, molecular defects and assisted reproductive techniques (ART)

Reciprocal regulation of miRNAs and piRNAs in embryonic development

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