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
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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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    • "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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    Molecular Reproduction and Development 07/2015; DOI:10.1002/mrd.22525 · 2.53 Impact Factor
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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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    Molecular cell 03/2015; 58(2). DOI:10.1016/j.molcel.2015.02.014 · 14.02 Impact Factor
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    • "The mir-35 family is unique among microRNAs across diverse species for its strong maternal effect. In vertebrates, microRNAs that are essential for embryogenesis, such as miR-430 in zebrafish and miR-290-295 in mice, are expressed abundantly only after the onset of zygotic transcription (Giraldez et al. 2006; Medeiros et al. 2011). Thus, the mir-35 family may represent a novel paradigm for microRNA control of embryogenesis. "
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