Mammalian E-type Cyclins Control Chromosome Pairing, Telomere Stability and CDK2 Localization in Male Meiosis

English version České info

Loss of function of cyclin E1 or E2, important regulators of the mitotic cell cycle, yields viable mice, but E2-deficient males display reduced fertility. To elucidate the role of E-type cyclins during spermatogenesis, we characterized their expression patterns and produced additional deletions of Ccne1 and Ccne2 alleles in the germline, revealing unexpected meiotic functions. While Ccne2 mRNA and protein are abundantly expressed in spermatocytes, Ccne1 mRNA is present but its protein is detected only at low levels. However, abundant levels of cyclin E1 protein are detected in spermatocytes deficient in cyclin E2 protein. Additional depletion of E-type cyclins in the germline resulted in increasingly enhanced spermatogenic abnormalities and corresponding decreased fertility and loss of germ cells by apoptosis. Profound meiotic defects were observed in spermatocytes, including abnormal pairing and synapsis of homologous chromosomes, heterologous chromosome associations, unrepaired double-strand DNA breaks, disruptions in telomeric structure and defects in cyclin-dependent-kinase 2 localization. These results highlight a new role for E-type cyclins as important regulators of male meiosis.

Vyšlo v časopise: Mammalian E-type Cyclins Control Chromosome Pairing, Telomere Stability and CDK2 Localization in Male Meiosis. PLoS Genet 10(2): e32767. doi:10.1371/journal.pgen.1004165
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004165

Souhrn

Zdroje

1. WolgemuthDJ (2008) Function of cyclins in regulating the mitotic and meiotic cell cycles in male germ cells. Cell Cycle 7: 3509–3513.

2. SweeneyC, MurphyM, KubelkaM, RavnikSE, HawkinsCF, et al. (1996) A distinct cyclin A is expressed in germ cells in the mouse. Development 122: 53–64.

3. LiuD, MatzukMM, SungWK, GuoQ, WangP, et al. (1998) Cyclin A1 is required for meiosis in the male mouse. Nat Genet 20: 377–380.

4. RavnikSE, WolgemuthDJ (1996) The developmentally restricted pattern of expression in the male germ line of a murine cyclin A, cyclin A2, suggests roles in both mitotic and meiotic cell cycles. Dev Biol 173: 69–78.

5. MurphyM, StinnakreMG, Senamaud-BeaufortC, WinstonNJ, SweeneyC, et al. (1997) Delayed early embryonic lethality following disruption of the murine cyclin A2 gene. Nat Genet 15: 83–86.

6. GengY, YuQ, SicinskaE, DasM, SchneiderJE, et al. (2003) Cyclin E ablation in the mouse. Cell 114: 431–443.

7. ParisiT, BeckAR, RougierN, McNeilT, LucianL, et al. (2003) Cyclins E1 and E2 are required for endoreplication in placental trophoblast giant cells. EMBO J 22: 4794–4803.

8. BellveAR, CavicchiaJC, MilletteCF, O'BrienDA, BhatnagarYM, et al. (1977) Spermatogenic cells of the prepuberal mouse. Isolation and morphological characterization. J Cell Biol 74: 68–85.

9. GengY, YuQ, WhoriskeyW, DickF, TsaiKY, et al. (2001) Expression of cyclins E1 and E2 during mouse development and in neoplasia. Proc Natl Acad Sci U S A 98: 13138–13143.

10. OdajimaJ, WillsZP, NdassaYM, TerunumaM, KretschmannovaK, et al. (2011) Cyclin E constrains Cdk5 activity to regulate synaptic plasticity and memory formation. Dev Cell 21: 655–668.

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

12. ChungSS, WangX, WolgemuthDJ (2005) Male sterility in mice lacking retinoic acid receptor alpha involves specific abnormalities in spermiogenesis. Differentiation 73: 188–198.

13. ManterolaM, PageJ, VascoC, BerriosS, ParraMT, et al. (2009) A high incidence of meiotic silencing of unsynapsed chromatin is not associated with substantial pachytene loss in heterozygous male mice carrying multiple simple robertsonian translocations. PLoS Genet 5: e1000625.

14. LiebeB, AlsheimerM, HoogC, BenaventeR, ScherthanH (2004) Telomere attachment, meiotic chromosome condensation, pairing, and bouquet stage duration are modified in spermatocytes lacking axial elements. Mol Biol Cell 15: 827–837.

15. Fernandez-CapetilloO, CelesteA, NussenzweigA (2003) Focusing on foci: H2AX and the recruitment of DNA-damage response factors. Cell Cycle 2: 426–427.

16. PageJ, de la FuenteR, ManterolaM, ParraMT, VieraA, et al. (2012) Inactivation or non-reactivation: what accounts better for the silence of sex chromosomes during mammalian male meiosis? Chromosoma 121: 307–326.

17. LiuFJ, BarchowskyA, OpreskoPL (2010) The Werner syndrome protein suppresses telomeric instability caused by chromium (VI) induced DNA replication stress. PLoS One 5: e11152.

18. WatsonLA, SolomonLA, LiJR, JiangY, EdwardsM, et al. (2013) Atrx deficiency induces telomere dysfunction, endocrine defects, and reduced life span. J Clin Invest 123: 2049–2063.

19. Mendez-BermudezA, HillsM, PickettHA, PhanAT, MergnyJL, et al. (2009) Human telomeres that contain (CTAGGG)n repeats show replication dependent instability in somatic cells and the male germline. Nucleic Acids Res 37: 6225–6238.

20. SurovtsevaYV, ChurikovD, BoltzKA, SongX, LambJC, et al. (2009) Conserved telomere maintenance component 1 interacts with STN1 and maintains chromosome ends in higher eukaryotes. Mol Cell 36: 207–218.

21. CesareAJ, HayashiMT, CrabbeL, KarlsederJ (2013) The telomere deprotection response is functionally distinct from the genomic DNA damage response. Mol Cell 51: 141–155.

22. AshleyT, WalpitaD, de RooijDG (2001) Localization of two mammalian cyclin dependent kinases during mammalian meiosis. J Cell Sci 114: 685–693.

23. NevzorovaYA, TschaharganehD, GasslerN, GengY, WeiskirchenR, et al. (2009) Aberrant cell cycle progression and endoreplication in regenerating livers of mice that lack a single E-type cyclin. Gastroenterology 137: 691–696, 691-703, 703, e691-696.

24. KauppiL, BarchiM, BaudatF, RomanienkoPJ, KeeneyS, et al. (2011) Distinct properties of the XY pseudoautosomal region crucial for male meiosis. Science 331: 916–920.

25. OrtegaS, PrietoI, OdajimaJ, MartinA, DubusP, et al. (2003) Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet 35: 25–31.

26. VieraA, RufasJS, MartinezI, BarberoJL, OrtegaS, et al. (2009) CDK2 is required for proper homologous pairing, recombination and sex-body formation during male mouse meiosis. J Cell Sci 122: 2149–2159.

27. GengY, LeeYM, WelckerM, SwangerJ, ZagozdzonA, et al. (2007) Kinase-independent function of cyclin E. Mol Cell 25: 127–139.

28. BernardsR (1999) CDK-independent activities of D type cyclins. Biochim Biophys Acta 1424: M17–22.

29. NguyenTB, ManovaK, CapodieciP, LindonC, BottegaS, et al. (2002) Characterization and expression of mammalian cyclin b3, a prepachytene meiotic cyclin. J Biol Chem 277: 41960–41969.

30. ScherthanH (2009) Analysis of telomere dynamics in mouse spermatogenesis. Methods Mol Biol 558: 383–399.

31. AdelfalkC, JanschekJ, RevenkovaE, BleiC, LiebeB, et al. (2009) Cohesin SMC1beta protects telomeres in meiocytes. J Cell Biol 187: 185–199.

32. SchmittJ, BenaventeR, HodzicD, HoogC, StewartCL, et al. (2007) Transmembrane protein Sun2 is involved in tethering mammalian meiotic telomeres to the nuclear envelope. Proc Natl Acad Sci U S A 104: 7426–7431.

33. AlsheimerM, LiebeB, SewellL, StewartCL, ScherthanH, et al. (2004) Disruption of spermatogenesis in mice lacking A-type lamins. J Cell Sci 117: 1173–1178.

34. DingX, XuR, YuJ, XuT, ZhuangY, et al. (2007) SUN1 is required for telomere attachment to nuclear envelope and gametogenesis in mice. Dev Cell 12: 863–872.

35. De LangeT (2005) Telomere-related genome instability in cancer. Cold Spring Harb Symp Quant Biol 70: 197–204.

36. SfeirA, de LangeT (2012) Removal of shelterin reveals the telomere end-protection problem. Science 336: 593–597.

37. SiderakisM, TarsounasM (2007) Telomere regulation and function during meiosis. Chromosome Res 15: 667–679.

38. EddyEM, WashburnTF, BunchDO, GouldingEH, GladenBC, et al. (1996) Targeted disruption of the estrogen receptor gene in male mice causes alteration of spermatogenesis and infertility. Endocrinology 137: 4796–4805.

39. ChungSS, WangX, RobertsSS, GriffeySM, ReczekPR, et al. (2011) Oral administration of a retinoic Acid receptor antagonist reversibly inhibits spermatogenesis in mice. Endocrinology 152: 2492–2502.

40. BerkovitsBD, WolgemuthDJ (2011) The first bromodomain of the testis-specific double bromodomain protein Brdt is required for chromocenter organization that is modulated by genetic background. Dev Biol 360: 358–368.

41. WolgemuthDJ, Gizang-GinsbergE, EngelmyerE, GavinBJ, PonzettoC (1985) Separation of mouse testis cells on a Celsep (TM) apparatus and their usefulness as a source of high molecular weight DNA or RNA. Gamete Res 12: 1–10.

42. ChalmelF, RollandAD, Niederhauser-WiederkehrC, ChungSS, DemouginP, et al. (2007) The conserved transcriptome in human and rodent male gametogenesis. Proc Natl Acad Sci U S A 104: 8346–8351.

43. PanigrahiSK, VasilevaA, WolgemuthDJ (2012) Sp1 Transcription Factor and GATA1 cis-Acting Elements Modulate Testis-Specific Expression of Mouse Cyclin A1. PLoS One 7: e47862.

44. ChungSS, SungW, WangX, WolgemuthDJ (2004) Retinoic acid receptor alpha is required for synchronization of spermatogenic cycles and its absence results in progressive breakdown of the spermatogenic process. Dev Dyn 230: 754–766.

45. Russell L, Ettlin R, Sinha Hikim A, Clegg E (1990) Histological and histopathological evaluation of the testis. Clearwater, Fl: Cache River Press.