#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Oligoasthenoteratozoospermia and Infertility in Mice Deficient for miR-34b/c and miR-449 Loci


The sustained production of functional motile sperm is critical for male fertility. In recent years, a dramatic increase of cases of male infertility were reported, with the most common cause represented by the production of morphologically abnormal spermatozoa with low motility. Several genetic and environmental factors have been proven to impact on sperm development. In particular, preliminary studies on samples from fertile and sterile individuals suggested that the deregulation of a class of small noncoding RNAs, called microRNAs, might be detrimental for sperm formation. To this end, we investigated the expression of Dicer, a core microRNA pathway component, in male germ cells and observed a peak of expression during meiosis. We performed a microRNA-expression screening and identified 5 members of the miR-34 family (miR-34bc and miR-449abc) as highly expressed from late meiosis to the sperm stage. Deletion of miR-34bc and miR-449 leads to sterility due to the production of abnormal spermatozoa with reduced motility. Thus our work proves for the first time the importance of a microRNA family in sperm formation and male fertility.


Vyšlo v časopise: Oligoasthenoteratozoospermia and Infertility in Mice Deficient for miR-34b/c and miR-449 Loci. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004597
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004597

Souhrn

The sustained production of functional motile sperm is critical for male fertility. In recent years, a dramatic increase of cases of male infertility were reported, with the most common cause represented by the production of morphologically abnormal spermatozoa with low motility. Several genetic and environmental factors have been proven to impact on sperm development. In particular, preliminary studies on samples from fertile and sterile individuals suggested that the deregulation of a class of small noncoding RNAs, called microRNAs, might be detrimental for sperm formation. To this end, we investigated the expression of Dicer, a core microRNA pathway component, in male germ cells and observed a peak of expression during meiosis. We performed a microRNA-expression screening and identified 5 members of the miR-34 family (miR-34bc and miR-449abc) as highly expressed from late meiosis to the sperm stage. Deletion of miR-34bc and miR-449 leads to sterility due to the production of abnormal spermatozoa with reduced motility. Thus our work proves for the first time the importance of a microRNA family in sperm formation and male fertility.


Zdroje

1. EddyEM (2002) Male germ cell gene expression. Recent Prog Horm Res 57: 103–128.

2. de RooijDG, RussellLD (2000) All you wanted to know about spermatogonia but were afraid to ask. J Androl 21: 776–798.

3. HandelMA, SchimentiJC (2010) Genetics of mammalian meiosis: regulation, dynamics and impact on fertility. Nat Rev Genet 11: 124–136.

4. MonesiV (1964) Ribonucleic Acid Synthesis during Mitosis and Meiosis in the Mouse Testis. J Cell Biol 22: 521–532.

5. ParonettoMP, MessinaV, BarchiM, GeremiaR, RichardS, et al. (2011) Sam68 marks the transcriptionally active stages of spermatogenesis and modulates alternative splicing in male germ cells. Nucleic Acids Res 39: 4961–4974.

6. O'CarrollD, SchaeferA (2013) General principals of miRNA biogenesis and regulation in the brain. Neuropsychopharmacology 38: 39–54.

7. LeeY, AhnC, HanJ, ChoiH, KimJ, et al. (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425: 415–419.

8. LandthalerM, YalcinA, TuschlT (2004) The human DiGeorge syndrome critical region gene 8 and Its D. melanogaster homolog are required for miRNA biogenesis. Curr Biol 14: 2162–2167.

9. BernsteinE, CaudyAA, HammondSM, HannonGJ (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409: 363–366.

10. HutvagnerG, McLachlanJ, PasquinelliAE, BalintE, TuschlT, et al. (2001) A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293: 834–838.

11. YiR, QinY, MacaraIG, CullenBR (2003) Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 17: 3011–3016.

12. MeisterG, LandthalerM, PetersL, ChenPY, UrlaubH, et al. (2005) Identification of novel argonaute-associated proteins. Curr Biol 15: 2149–2155.

13. SchwarzDS, HutvagnerG, HaleyB, ZamorePD (2002) Evidence that siRNAs function as guides, not primers, in the Drosophila and human RNAi pathways. Mol Cell 10: 537–548.

14. GrimsonA, FarhKK, JohnstonWK, Garrett-EngeleP, LimLP, et al. (2007) MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27: 91–105.

15. DoenchJG, SharpPA (2004) Specificity of microRNA target selection in translational repression. Genes Dev 18: 504–511.

16. AmbrosV, BartelB, BartelDP, BurgeCB, CarringtonJC, et al. (2003) A uniform system for microRNA annotation. RNA 9: 277–279.

17. Behm-AnsmantI, RehwinkelJ, DoerksT, StarkA, BorkP, et al. (2006) mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes Dev 20: 1885–1898.

18. OrbanTI, IzaurraldeE (2005) Decay of mRNAs targeted by RISC requires XRN1, the Ski complex, and the exosome. RNA 11: 459–469.

19. FarhKK, GrimsonA, JanC, LewisBP, JohnstonWK, et al. (2005) The widespread impact of mammalian MicroRNAs on mRNA repression and evolution. Science 310: 1817–1821.

20. BaekD, VillenJ, ShinC, CamargoFD, GygiSP, et al. (2008) The impact of microRNAs on protein output. Nature 455: 64–71.

21. LimLP, LauNC, Garrett-EngeleP, GrimsonA, SchelterJM, et al. (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433: 769–773.

22. YangJS, MaurinT, RobineN, RasmussenKD, JeffreyKL, et al. (2010) Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2-mediated microRNA biogenesis. Proc Natl Acad Sci U S A 107: 15163–15168.

23. CheloufiS, Dos SantosCO, ChongMM, HannonGJ (2010) A dicer-independent miRNA biogenesis pathway that requires Ago catalysis. Nature 465: 584–589.

24. CifuentesD, XueH, TaylorDW, PatnodeH, MishimaY, et al. (2010) A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity. Science 328: 1694–1698.

25. BabiarzJE, RubyJG, WangY, BartelDP, BlellochR (2008) Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor-independent, Dicer-dependent small RNAs. Genes Dev 22: 2773–2785.

26. WatanabeT, TotokiY, ToyodaA, KanedaM, Kuramochi-MiyagawaS, et al. (2008) Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature 453: 539–543.

27. TamOH, AravinAA, SteinP, GirardA, MurchisonEP, et al. (2008) Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes. Nature 453: 534–538.

28. HayashiK, Chuva de Sousa LopesSM, KanedaM, TangF, HajkovaP, et al. (2008) MicroRNA biogenesis is required for mouse primordial germ cell development and spermatogenesis. PLoS One 3: e1738.

29. Sadate-NgatchouPI, PayneCJ, DearthAT, BraunRE (2008) Cre recombinase activity specific to postnatal, premeiotic male germ cells in transgenic mice. Genesis 46: 738–742.

30. HobbsRM, FagooneeS, PapaA, WebsterK, AltrudaF, et al. (2012) Functional antagonism between Sall4 and Plzf defines germline progenitors. Cell Stem Cell 10: 284–298.

31. YiR, O'CarrollD, PasolliHA, ZhangZ, DietrichFS, et al. (2006) Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs. Nat Genet 38: 356–362.

32. BaoJ, LiD, WangL, WuJ, HuY, et al. (2012) MicroRNA-449 and microRNA-34b/c function redundantly in murine testes by targeting E2F transcription factor-retinoblastoma protein (E2F-pRb) pathway. J Biol Chem 287: 21686–21698.

33. HeL, HeX, LimLP, de StanchinaE, XuanZ, et al. (2007) A microRNA component of the p53 tumour suppressor network. Nature 447: 1130–1134.

34. ChoiYJ, LinCP, HoJJ, HeX, OkadaN, et al. (2011) miR-34 miRNAs provide a barrier for somatic cell reprogramming. Nat Cell Biol 13: 1353–1360.

35. ConcepcionCP, HanYC, MuP, BonettiC, YaoE, et al. (2012) Intact p53-dependent responses in miR-34-deficient mice. PLoS Genet 8: e1002797.

36. BoonRA, IekushiK, LechnerS, SeegerT, FischerA, et al. (2013) MicroRNA-34a regulates cardiac ageing and function. Nature 495: 107–110.

37. HirshA (2003) Male subfertility. BMJ 327: 669–672.

38. BastosH, LassalleB, ChicheporticheA, RiouL, TestartJ, et al. (2005) Flow cytometric characterization of viable meiotic and postmeiotic cells by Hoechst 33342 in mouse spermatogenesis. Cytometry A 65: 40–49.

39. Di GiacomoM, ComazzettoS, SainiH, De FazioS, CarrieriC, et al. (2013) Multiple epigenetic mechanisms and the piRNA pathway enforce LINE1 silencing during adult spermatogenesis. Mol Cell 50: 601–608.

40. Martin-de-LaraF, Sanchez-AparicioP, Arias de la FuenteC, Rey-CamposJ (2008) Biological effects of FoxJ2 over-expression. Transgenic Res 17: 1131–1141.

41. De FazioS, BartonicekN, Di GiacomoM, Abreu-GoodgerC, SankarA, et al. (2011) The endonuclease activity of Mili fuels piRNA amplification that silences LINE1 elements. Nature 480: 259–263.

42. FarleyFW, SorianoP, SteffenLS, DymeckiSM (2000) Widespread recombinase expression using FLPeR (flipper) mice. Genesis 28: 106–110.

43. SchwenkF, BaronU, RajewskyK (1995) A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res 23: 5080–5081.

44. MahadevaiahSK, TurnerJM, BaudatF, RogakouEP, de BoerP, et al. (2001) Recombinational DNA double-strand breaks in mice precede synapsis. Nat Genet 27: 271–276.

45. SmythGK (2004) Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3: Article3.

46. SmythGK, MichaudJ, ScottHS (2005) Use of within-array replicate spots for assessing differential expression in microarray experiments. Bioinformatics 21: 2067–2075.

47. IrizarryRA, HobbsB, CollinF, Beazer-BarclayYD, AntonellisKJ, et al. (2003) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4: 249–264.

48. van DongenS, Abreu-GoodgerC, EnrightAJ (2008) Detecting microRNA binding and siRNA off-target effects from expression data. Nat Methods 5: 1023–1025.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2014 Číslo 10
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#