Mir-290-295 deficiency in mice results in partially penetrant embryonic lethality and germ cell defects

Whitehead Institute for Biomedical Research, Cambridge, MA 02139, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2011; 108(34):14163-8. DOI: 10.1073/pnas.1111241108
Source: PubMed


Mir-290 through mir-295 (mir-290-295) is a mammalian-specific microRNA (miRNA) cluster that, in mice, is expressed specifically in early embryos and embryonic germ cells. Here, we show that mir-290-295 plays important roles in embryonic development as indicated by the partially penetrant lethality of mutant embryos. In addition, we show that in surviving mir-290-295-deficient embryos, female but not male fertility is compromised. This impairment in fertility arises from a defect in migrating primordial germ cells and occurs equally in male and female mutant animals. Male mir-290-295(-/-) mice, due to the extended proliferative lifespan of their germ cells, are able to recover from this initial germ cell loss and are fertile. Female mir-290-295(-/-) mice are unable to recover and are sterile, due to premature ovarian failure.

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    • "PGC-specific deficiency of Dicer, which plays a key role in microRNA biogenesis, results in poor PGC proliferation (Hayashi et al., 2008). MiR-290-295 cluster deficiency in mice results in embryonic lethality and germ cell defects with impaired PGC migration and premature ovarian failure (Medeiros et al., 2011). MiR-29b promotes female PGC development by targeting de novo DNA methyltransferase Dnmt3a and Dnmt3b (Takada et al., 2009). "
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    ABSTRACT: Non-coding microRNAs (miRNAs) regulate the translation of target messenger RNAs (mRNAs) involved in the growth and development of a variety of cells, including primordial germ cells (PGCs) which play an essential role in germ cell development. However, the target mRNAs and the regulatory networks influenced by miRNAs in PGCs remain unclear. Here, we demonstrate a novel miRNAs control PGC development through targeting mRNAs involved in various cellular pathways. We reveal the PGC-enriched expression patterns of nine miRNAs, including miR-10b, -18a, -93, -106b, -126-3p, -127, -181a, -181b, and -301, using miRNA expression analysis along with mRNA microarray analysis in PGCs, embryonic gonads, and postnatal testes. These miRNAs are highly expressed in PGCs, as demonstrated by Northern blotting, miRNA in situ hybridization assay, and miRNA qPCR analysis. This integrative study utilizing mRNA microarray analysis and miRNA target prediction demonstrates the regulatory networks through which these miRNAs regulate their potential target genes during PGC development. The elucidated networks of miRNAs disclose a coordinated molecular mechanism by which these miRNAs regulate distinct cellular pathways in PGCs that determine germ cell development.1.
    Full-text · Article · Oct 2015 · Moleculer Cells
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    • "tionembryos(McCallieetal.,2010;Rosenbluthetal., 2013),aswellasinelongatedclonedandinvitro-produced bovineembryosretrievedfromrecipientcattle(Castro etal.,2010). AnassortmentofmiRNAshavebeenidentifiedin individually-culturedhumanblastocysts,andtheirprofiles appeartobesex-specificaswellasexhibitdifferences betweeneuploidandaneuploidblastocystsÀÀnamely, aneuploidblastocystsconsistentlyexpressapanelof miRNAsatlevelslowerthantheireuploidcounterparts (Rosenbluthetal.,2013).Basedontheseobservations, miRNAabundancemayprovideaprognosisforembryo survivalaswellasforveryearlyembryonicdevelopment andsexdifferentiation.Forexample,miR-372asthemost highlyexpressedmiRNAdetectableinhumanblastocysts (Rosenbluthetal.,2013).Itsmurinehomolog(themiR- 290À295cluster)isspecificallyexpressedinearlyem- bryosandgermcellsofadultgonads,anditsdepletion resultsinfemaleinfertilityduetoprematureovarianfailure (Medeirosetal.,2011).Asubsequentstudyidentified miR-372andmiR-191inculturemediumfromcryopre- servedpronuclearhumanembryos,wheretheexpression ofmiR-191ismarkedlyhigherinmediumsurrounding aneuploidblastocysts(Rosenbluthetal.,2014).Quantifi- cationofthesemiRNAsinculturemediumfromacohort ofpatientsundergoingfreshsingle-embryotransferIVF cyclesrevealedsimilarmiRNAprofiles,withmiR-191and miR-372moreabundantinculturemediumfromfailed- IVF-cycleembryosthanmediumfromembryosthatresultedinlivebirths(Rosenbluthetal.,2014).Thepres- enceofmiR-372insidehigh-qualityblastocystsversusits presenceintheculturemediumoffailedembryossug- gestsamechanismwherecertainmiRNAsarerequired forearlyembryonicsurvival;theirreleaseintosurround- ingculturemediummaybeindicativeofdevelopmental arrest.Interestingly,thesedifferenceswereonlyfound whenembryoswerefertilizedbystandardinsemination. Theculturemediumofembryosfertilizedbyintracytoplasmicsperminjection(ICSI),ontheotherhand,con- tainedmoremiRNAregardlessofpregnancyoutcome, suggestingthatthephysicaltraumatothezonapellucida andoocytecytoplasmcouldcausemiRNAtoleakfrom theembryosandmayprecludetheuseofmiRNAsasa diagnostictoolforthisparticularfertilizationmethod (Rosenbluthetal.,2014).Althoughresearchdirectedat bovinemiRNAspresentinculturemediahasonlyrecently begun,earlyfindingsindicatethatmiR-25ÀÀamicroRNA expressedindegeneratebovineembryosÀÀispresentin invitroculturemediumofbovineblastocysts(Kroppetal., 2014),andcouldthereforeserveasabiomarkerof embryoquality. "
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    ABSTRACT: Animal reproductive biotechnology is continually evolving. Significant advances have been made in our understanding of early embryonic mortality and embryo development in domestic animals, which has improved the selection and success of in vitro technologies. Yet our knowledge is still relatively limited such that identifying a single embryo with the highest chance of survival and development for transfer remains challenging. While invasive methods such as embryo biopsy can provide useful information regarding the genetic status of the embryos, morphological assessment remains the most common method for embryo evaluation. A recent shift, however, favors alternative, adjunct methods for non-invasive assessment of an embryo's viability and developmental potential. Various analytical techniques have facilitated the evaluation of cellular health through the metabolome, the assessment of end products of cellular metabolism, or by analyzing spent media for small RNAs. This review discusses the application of non-invasive approaches for ascertaining the health and viability of in vitro-produced bovine embryos. A comparative analysis of non-invasive techniques for embryo assessment currently being investigated in cattle and humans is also discussed. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jul 2015 · Molecular Reproduction and Development
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    • "Please cite this article in press as: Hnisz et al., Convergence of Developmental and Oncogenic Signaling Pathways at Transcriptional Super-Enhancers, Molecular Cell (2015), self-renewal, pluripotency, and differentiation (Hall et al., 2009; Ma et al., 2011; Medeiros et al., 2011; Nichols et al., 1998; Romito et al., 2010). The five super-enhancers show physical interactions with their respective associated genes and are located within insulated neighborhoods in the ESC genome (Figure S1C) (Dowen et al., 2014), suggesting that these genes represent the bona fide physiological targets of the five SEs. "
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    ABSTRACT: Super-enhancers and stretch enhancers (SEs) drive expression of genes that play prominent roles in normal and disease cells, but the functional importance of these clustered enhancer elements is poorly understood, so it is not clear why genes key to cell identity have evolved regulation by such elements. Here, we show that SEs consist of functional constituent units that concentrate multiple developmental signaling pathways at key pluripotency genes in embryonic stem cells and confer enhanced responsiveness to signaling of their associated genes. Cancer cells frequently acquire SEs at genes that promote tumorigenesis, and we show that these genes are especially sensitive to perturbation of oncogenic signaling pathways. Super-enhancers thus provide a platform for signaling pathways to regulate genes that control cell identity during development and tumorigenesis. Copyright © 2015 Elsevier Inc. All rights reserved.
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