Mutations in the MOV10L1 ATP Hydrolysis Motif Cause piRNA Biogenesis Failure and Male Sterility in Mice

Fu, Qi; Pandey, Radha Raman; Leu, N. Adrian; Pillai, Ramesh S.; Wang, P. Jeremy

doi:10.1095/biolreprod.116.142430

Cited by 25 publications

(25 citation statements)

References 54 publications

(113 reference statements)

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“…We first tested Armitage (Armi) which is a highly conserved RNA helicase that is essential for production of all piRNAs in flies [ 15 , 21 ]. Its orthologue MOV10L1 has a similar role in mice [ 22 – 25 ]. Transgenic fly lines co-expressing both the BoxB reporter and NHA-Armi (with the N-peptide and an HA-tag), specifically in the fly ovarian soma [under control of the traffic jam -GAL4 driver ( tj -GAL4)] were generated.…”

Section: Resultsmentioning

confidence: 99%

“…Among these, Armi is highly conserved and works in all the systems tested: fly ovarian soma and germline, and in the OSC cultures. Armi [ 14 , 15 , 21 ] and its mouse orthologue MOV10L1 [ 22 – 25 ] are absolutely essential for biogenesis of all piRNAs in flies and mice. In contrast, Yb is restricted to Drosophila , pointing to a non-conserved role for the protein in the fly somatic follicle cells [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

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Recruitment of Armitage and Yb to a transcript triggers its phased processing into primary piRNAs in Drosophila ovaries

et al. 2017

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Small RNAs called PIWI -interacting RNAs (piRNAs) are essential for transposon control and fertility in animals. Primary processing is the small RNA biogenesis pathway that uses long single-stranded RNA precursors to generate millions of individual piRNAs, but the molecular mechanisms that identify a transcript as a precursor are poorly understood. Here we demonstrate that artificial tethering of the piRNA biogenesis factor, Armi, to a transcript is sufficient to direct it into primary processing in Drosophila ovaries and in an ovarian cell culture model. In the fly ovarian somatic follicle cells, the transcript becomes cleaved in a stepwise manner, with a 5′→3′ directionality, liberating U1-containing ~24 nt piRNAs that are loaded into Piwi. Although uridines are preferred for generation of piRNA 5′ ends, processing takes place even in their absence, albeit at a lower efficiency. We show that recombinant Armi has 5′→3′ helicase activity, and mutations that abolish this activity also reduce piRNA processing in vivo. Another somatic piRNA pathway factor Yb, an interactor of Armi, is also able to trigger piRNA biogenesis when tethered to a transcript. Tethering-mediated primary piRNA biogenesis is also functional in the fly ovarian germline and loads all the three PIWI proteins present in this environment. Our study finds a broad correlation between piRNA processing and localization of the tethered factors to the cytoplasmic perinuclear ribonucleoprotein granules called germline nuage or somatic Yb bodies. We conclude that transcripts bound by Armi and Yb are identified as piRNA precursors, resulting in localization to cytoplasmic processing granules and their subsequent engagement by the resident piRNA biogenesis machinery.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Recruitment of Armitage and Yb to a transcript triggers its phased processing into primary piRNAs in Drosophila ovaries

et al. 2017

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“…Primary transcript secondary structure does not appear to be a requirement for piRNA biogenesis [ 67 ], although a role for the RNA helicase MOV10L1/Armitage in unwinding localised secondary structures of piRNA precursors in mice and Drosophila has been described [ 68 , 69 ]. Orthologues of this helicase can be found in Amphimedon (NCBI: XP_019853676.1), Nematostella (NCBI: XP_001626596.1, XP_001637169.1) and Mnemiopsis (NHGRI: ML005359a).…”

Section: Discussionmentioning

confidence: 99%

Diverse RNA interference strategies in early-branching metazoans

2018

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BackgroundMicro RNAs (miRNAs) and piwi interacting RNAs (piRNAs), along with the more ancient eukaryotic endogenous small interfering RNAs (endo-siRNAs) constitute the principal components of the RNA interference (RNAi) repertoire of most animals. RNAi in non-bilaterians – sponges, ctenophores, placozoans and cnidarians - appears to be more diverse than that of bilaterians, and includes structurally variable miRNAs in sponges, an enormous number of piRNAs in cnidarians and the absence of miRNAs in ctenophores and placozoans.ResultsHere we identify thousands of endo-siRNAs and piRNAs from the sponge Amphimedon queenslandica, the ctenophore Mnemiopsis leidyi and the cnidarian Nematostella vectensis using a computational approach that clusters mapped small RNA sequences and annotates each cluster based on the read length and relative abundance of the constituent reads. This approach was validated on 11 small RNA libraries in Drosophila melanogaster, demonstrating the successful annotation of RNAi-associated loci with properties consistent with previous reports. In the non-bilaterians we uncover seven new miRNAs from Amphimedon and four from Nematostella as well as sub-populations of candidate cis-natural antisense transcript (cis-NAT) endo-siRNAs. We confirmed the absence of miRNAs in Mnemiopsis but detected an abundance of endo-siRNAs in this ctenophore. Analysis of putative piRNA structure suggests that conserved localised secondary structures in primary transcripts may be important for the production of mature piRNAs in Amphimedon and Nematostella, as is also the case for endo-siRNAs.ConclusionTogether, these findings suggest that the last common ancestor of extant animals did not have the entrained RNAi system that typifies bilaterians. Instead it appears that bilaterians, cnidarians, ctenophores and sponges express unique repertoires and combinations of miRNAs, piRNAs and endo-siRNAs.Electronic supplementary materialThe online version of this article (10.1186/s12862-018-1274-2) contains supplementary material, which is available to authorized users.

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“…PIWI proteins are primarily expressed in germ cells and in both mouse and fruit fly, mutations of genes encoding PIWI proteins result in de-repression of TEs in the germline, leading to male sterility (24,25). PiRNA expression in rat testes has previously been reported to be responsive to testosterone exposure, and this response has been postulated as one of the mechanisms that allows testosterone to regulate testis function (26,27).…”

Section: Discussionmentioning

confidence: 99%

Androgen-responsive non-coding small RNAs extend the potential of HCG stimulation to act as a bioassay of androgen sufficiency

Rodie

Mudaliar²,

Herzyk

et al. 2017

European Journal of Endocrinology

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Background: It is unclear whether a short-term change in circulating androgens is associated with changes in the transcriptome of the peripheral blood mononuclear cells (PBMC). Aims and methods:To explore the effect of hCG stimulation on the PBMC transcriptome, 12 boys with a median age (range) of 0.7 years (0.3, 11.2) who received intramuscular hCG 1500u on 3 consecutive days as part of their investigations underwent transcriptomic array analysis on RNA extracted from peripheral blood mononuclear cells before and after hCG stimulation. Results: Median pre-and post-hCG testosterone for the overall group was 0.7 nmol/L (<0.5, 6) and 7.9 nmol/L (<0.5, 31.5), respectively. Of the 12 boys, 3 (25%) did not respond to hCG stimulation with a pre and post median serum testosterone of <0.5 nmol/L and <0.5 nmol/L, respectively. When corrected for gene expression changes in the nonresponders to exclude hCG effects, all 9 of the hCG responders consistently demonstrated a 20% or greater increase in the expression of piR-37153 and piR-39248, non-coding PIWI-interacting RNAs (piRNAs). In addition, of the 9 responders, 8, 6 and 4 demonstrated a 30, 40 and 50% rise, respectively, in a total of 2 further piRNAs. In addition, 3 of the responders showed a 50% or greater rise in the expression of another small RNA, SNORD5. On comparing fold-change in serum testosterone with fold-change in the above transcripts, a positive correlation was detected for SNORD5 (P = 0.01). Conclusions: The identification of a dynamic and androgen-responsive PBMC transcriptome extends the potential value of the hCG test for the assessment of androgen sufficiency.

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Mutations in the MOV10L1 ATP Hydrolysis Motif Cause piRNA Biogenesis Failure and Male Sterility in Mice

Cited by 25 publications

References 54 publications

Recruitment of Armitage and Yb to a transcript triggers its phased processing into primary piRNAs in Drosophila ovaries

Recruitment of Armitage and Yb to a transcript triggers its phased processing into primary piRNAs in Drosophila ovaries

Diverse RNA interference strategies in early-branching metazoans

Androgen-responsive non-coding small RNAs extend the potential of HCG stimulation to act as a bioassay of androgen sufficiency

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