A Critical Function of Mad2l2 in Primordial Germ Cell Development of Mice

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The development of primordial germ cells (PGCs) involves several waves of epigenetic reprogramming. A major step is following specification and involves the transition from the stably suppressive histone modification H3K9me2 to the more flexible, still repressive H3K27me3, while PGCs are arrested in G2 phase of their cycle. The significance and underlying molecular mechanism of this transition were so far unknown. Here, we generated mutant mice for the Mad2l2 (Mad2B, Rev7) gene product, and found that they are infertile in both males and females. We demonstrated that Mad2l2 is essential for PGC, but not somatic development. PGCs were specified normally in Mad2l2^−/− embryos, but became eliminated by apoptosis during the subsequent phase of epigenetic reprogramming. A majority of knockout PGCs failed to arrest in the G2 phase, and did not switch from a H3K9me2 to a H3K27me3 configuration. By the analysis of transfected fibroblasts we found that the interaction of Mad2l2 with the histone methyltransferases G9a and GLP lead to a downregulation of H3K9me2. The inhibitory binding of Mad2l2 to Cyclin dependent kinase 1 (Cdk1) could arrest the cell cycle in the G2 phase, and also allowed another histone methyltransferase, Ezh2, to upregulate H3K27me3. Together, these results demonstrate the potential of Mad2l2 in the regulation of both cell cycle and the epigenetic status. The function of Mad2l2 is essential in PGCs, and thus of high relevance for fertility.

Vyšlo v časopise: A Critical Function of Mad2l2 in Primordial Germ Cell Development of Mice. PLoS Genet 9(8): e32767. doi:10.1371/journal.pgen.1003712
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003712

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Zdroje

1. SaitouM, YamajiM (2010) Germ cell specification in mice: signaling, transcription regulation, and epigenetic consequences. Reproduction 139 : 931–942.

2. HajkovaP, AncelinK, WaldmannT, LacosteN, LangeUC, et al. (2008) Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature 452 : 877–881.

3. SekiY, HayashiK, ItohK, MizugakiM, SaitouM, et al. (2005) Extensive and orderly reprogramming of genome-wide chromatin modifications associated with specification and early development of germ cells in mice. Dev Biol 278 : 440–458.

4. OhinataY, PayerB, O'CarrollD, AncelinK, OnoY, et al. (2005) Blimp1 is a critical determinant of the germ cell lineage in mice. Nature 436 : 207–213.

5. YamajiM, SekiY, KurimotoK, YabutaY, YuasaM, et al. (2008) Critical function of Prdm14 for the establishment of the germ cell lineage in mice. Nat Genet 40 : 1016–1022.

6. AvilionAA, NicolisSK, PevnyLH, PerezL, VivianN, et al. (2003) Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 17 : 126–140.

7. KurimotoK, YabutaY, OhinataY, ShigetaM, YamanakaK, et al. (2008) Complex genome-wide transcription dynamics orchestrated by Blimp1 for the specification of the germ cell lineage in mice. Genes Dev 22 : 1617–1635.

8. PirouzM, KlimkeA, KesselM (2012) The reciprocal relationship between primordial germ cells and pluripotent stem cells. J Mol Med (Berl) 90 : 753–761.

9. MatsuiY, ZseboK, HoganBL (1992) Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture. Cell 70 : 841–847.

10. ResnickJL, BixlerLS, ChengL, DonovanPJ (1992) Long-term proliferation of mouse primordial germ cells in culture. Nature 359 : 550–551.

11. SekiY, YamajiM, YabutaY, SanoM, ShigetaM, et al. (2007) Cellular dynamics associated with the genome-wide epigenetic reprogramming in migrating primordial germ cells in mice. Development 134 : 2627–2638.

12. HackettJA, SenguptaR, ZyliczJJ, MurakamiK, LeeC, et al. (2012) Germline DNA Demethylation Dynamics and Imprint Erasure Through 5-Hydroxymethylcytosine. Science 339 : 448–452.

13. TachibanaM, UedaJ, FukudaM, TakedaN, OhtaT, et al. (2005) Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. Genes Dev 19 : 815–826.

14. KuzmichevA, NishiokaK, Erdjument-BromageH, TempstP, ReinbergD (2002) Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev 16 : 2893–2905.

15. CaoR, WangL, WangH, XiaL, Erdjument-BromageH, et al. (2002) Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298 : 1039–1043.

16. ChenS, BohrerLR, RaiAN, PanY, GanL, et al. (2010) Cyclin-dependent kinases regulate epigenetic gene silencing through phosphorylation of EZH2. Nat Cell Biol 12 : 1108–1114.

17. KanekoS, LiG, SonJ, XuCF, MargueronR, et al. (2010) Phosphorylation of the PRC2 component Ezh2 is cell cycle-regulated and up-regulates its binding to ncRNA. Genes Dev 24 : 2615–2620.

18. WeiY, ChenYH, LiLY, LangJ, YehSP, et al. (2011) CDK1-dependent phosphorylation of EZH2 suppresses methylation of H3K27 and promotes osteogenic differentiation of human mesenchymal stem cells. Nat Cell Biol 13 : 87–94.

19. HayashiK, OhtaH, KurimotoK, AramakiS, SaitouM (2011) Reconstitution of the Mouse Germ Cell Specification Pathway in Culture by Pluripotent Stem Cells. Cell 146 : 519–532.

20. HyldigSM, CroxallN, ContrerasDA, ThomsenPD, AlberioR (2011) Epigenetic reprogramming in the porcine germ line. BMC Dev Biol 11 : 11.

21. De FeliciM, FariniD (2012) The control of cell cycle in mouse primordial germ cells: old and new players. Curr Pharm Des 18 : 233–244.

22. AravindL, KooninEV (1998) The HORMA domain: a common structural denominator in mitotic checkpoints, chromosome synapsis and DNA repair. Trends Biochem Sci 23 : 284–286.

23. ChenJ, FangG (2001) MAD2B is an inhibitor of the anaphase-promoting complex. Genes Dev 15 : 1765–1770.

24. PflegerCM, SalicA, LeeE, KirschnerMW (2001) Inhibition of Cdh1-APC by the MAD2-related protein MAD2L2: a novel mechanism for regulating Cdh1. Genes Dev 15 : 1759–1764.

25. CheungHW, ChunAC, WangQ, DengW, HuL, et al. (2006) Inactivation of human MAD2B in nasopharyngeal carcinoma cells leads to chemosensitization to DNA-damaging agents. Cancer Res 66 : 4357–4367.

26. GanGN, WittschiebenJP, WittschiebenBO, WoodRD (2008) DNA polymerase zeta (pol zeta) in higher eukaryotes. Cell Res 18 : 174–183.

27. HanafusaT, HabuT, TomidaJ, OhashiE, MurakumoY, et al. (2010) Overlapping in short motif sequences for binding to human REV7 and MAD2 proteins. Genes Cells 15 : 281–296.

28. MurakumoY, OguraY, IshiiH, NumataS, IchiharaM, et al. (2001) Interactions in the error-prone postreplication repair proteins hREV1, hREV3, and hREV7. J Biol Chem 276 : 35644–35651.

29. ZhangL, YangSH, SharrocksAD (2007) Rev7/MAD2B links c-Jun N-terminal protein kinase pathway signaling to activation of the transcription factor Elk-1. Mol Cell Biol 27 : 2861–2869.

30. MedendorpK, VreedeL, van GroningenJJ, HetterschijtL, BrugmansL, et al. (2010) The mitotic arrest deficient protein MAD2B interacts with the clathrin light chain A during mitosis. PLoS One 5: e15128.

31. MedendorpK, van GroningenJJ, VreedeL, HetterschijtL, van den HurkWH, et al. (2009) The mitotic arrest deficient protein MAD2B interacts with the small GTPase RAN throughout the cell cycle. PLoS One 4: e7020.

32. HongCF, ChouYT, LinYS, WuCW (2009) MAD2B, a novel TCF4-binding protein, modulates TCF4-mediated epithelial-mesenchymal transdifferentiation. J Biol Chem 284 : 19613–19622.

33. CostoyaJA, HobbsRM, BarnaM, CattorettiG, ManovaK, et al. (2004) Essential role of Plzf in maintenance of spermatogonial stem cells. Nat Genet 36 : 653–659.

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

35. Oulad-AbdelghaniM, BouilletP, DecimoD, GansmullerA, HeybergerS, et al. (1996) Characterization of a premeiotic germ cell-specific cytoplasmic protein encoded by Stra8, a novel retinoic acid-responsive gene. J Cell Biol 135 : 469–477.

36. HamerG, Roepers-GajadienHL, van Duyn-GoedhartA, GademanIS, KalHB, et al. (2003) DNA double-strand breaks and gamma-H2AX signaling in the testis. Biol Reprod 68 : 628–634.

37. DameC, KirschnerKM, BartzKV, WallachT, HusselsCS, et al. (2006) Wilms tumor suppressor, Wt1, is a transcriptional activator of the erythropoietin gene. Blood 107 : 4282–4290.

38. RogatschH, JezekD, HittmairA, MikuzG, FeichtingerH (1996) Expression of vimentin, cytokeratin, and desmin in Sertoli cells of human fetal, cryptorchid, and tumour-adjacent testicular tissue. Virchows Arch 427 : 497–502.

39. ScholerHR, DresslerGR, BallingR, RohdewohldH, GrussP (1990) Oct-4: a germline-specific transcription factor mapping to the mouse t-complex. EMBO J 9 : 2185–2195.

40. SakaguchiK, HerreraJE, SaitoS, MikiT, BustinM, et al. (1998) DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev 12 : 2831–2841.

41. GuY, RunyanC, ShoemakerA, SuraniA, WylieC (2009) Steel factor controls primordial germ cell survival and motility from the time of their specification in the allantois, and provides a continuous niche throughout their migration. Development 136 : 1295–1303.

42. GoudarziM, BanischTU, MobinMB, MaghelliN, TarbashevichK, et al. (2012) Identification and Regulation of a Molecular Module for Bleb-Based Cell Motility. Dev Cell 23 : 210–8.

43. DoitsidouM, Reichman-FriedM, SteblerJ, KoprunnerM, DorriesJ, et al. (2002) Guidance of primordial germ cell migration by the chemokine SDF-1. Cell 111 : 647–659.

44. SaitouM (2009) Specification of the germ cell lineage in mice. Front Biosci 14 : 1068–1087.

45. NaicheLA, PapaioannouVE (2007) Cre activity causes widespread apoptosis and lethal anemia during embryonic development. Genesis 45 : 768–775.

46. YabutaY, KurimotoK, OhinataY, SekiY, SaitouM (2006) Gene expression dynamics during germline specification in mice identified by quantitative single-cell gene expression profiling. Biol Reprod 75 : 705–716.

47. JackmanM, LindonC, NiggEA, PinesJ (2003) Active cyclin B1-Cdk1 first appears on centrosomes in prophase. Nat Cell Biol 5 : 143–148.

48. LindqvistA, van ZonW, Karlsson RosenthalC, WolthuisRM (2007) Cyclin B1-Cdk1 activation continues after centrosome separation to control mitotic progression. PLoS Biol 5: e123.

49. PinesJ, HunterT (1991) Human cyclins A and B1 are differentially located in the cell and undergo cell cycle-dependent nuclear transport. J Cell Biol 115 : 1–17.

50. LindqvistA, Rodriguez-BravoV, MedemaRH (2009) The decision to enter mitosis: feedback and redundancy in the mitotic entry network. J Cell Biol 185 : 193–202.

51. ZhanQ, AntinoreMJ, WangXW, CarrierF, SmithML, et al. (1999) Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene 18 : 2892–2900.

52. WeberS, EckertD, NettersheimD, GillisAJ, SchaferS, et al. (2010) Critical function of AP-2 gamma/TCFAP2C in mouse embryonic germ cell maintenance. Biol Reprod 82 : 214–223.

53. KehlerJ, TolkunovaE, KoschorzB, PesceM, GentileL, et al. (2004) Oct4 is required for primordial germ cell survival. EMBO Rep 5 : 1078–1083.

54. RunyanC, SchaibleK, MolyneauxK, WangZ, LevinL, et al. (2006) Steel factor controls midline cell death of primordial germ cells and is essential for their normal proliferation and migration. Development 133 : 4861–4869.

55. TachibanaM, MatsumuraY, FukudaM, KimuraH, ShinkaiY (2008) G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription. EMBO J 27 : 2681–2690.

56. TachibanaM, NozakiM, TakedaN, ShinkaiY (2007) Functional dynamics of H3K9 methylation during meiotic prophase progression. EMBO J 26 : 3346–3359.

57. EstevePO, ChinHG, SmallwoodA, FeeheryGR, GangisettyO, et al. (2006) Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. Genes Dev 20 : 3089–3103.

58. HackettJA, ZyliczJJ, SuraniMA (2012) Parallel mechanisms of epigenetic reprogramming in the germline. Trends Genet 28 : 164–174.

59. YamajiM, UedaJ, HayashiK, OhtaH, YabutaY, et al. (2013) PRDM14 Ensures Naive Pluripotency through Dual Regulation of Signaling and Epigenetic Pathways in Mouse Embryonic Stem Cells. Cell Stem Cell 12 : 368–382.

60. YamaneK, ToumazouC, TsukadaY, Erdjument-BromageH, TempstP, et al. (2006) JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell 125 : 483–495.

61. MagnusdottirE, GillichA, GraboleN, SuraniMA (2012) Combinatorial control of cell fate and reprogramming in the mammalian germline. Curr Opin Genet Dev 22 : 466–74.

62. HutchinsJR, ToyodaY, HegemannB, PoserI, HericheJK, et al. (2010) Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science 328 : 593–599.

63. ShinkaiY, TachibanaM (2011) H3K9 methyltransferase G9a and the related molecule GLP. Genes Dev 25 : 781–788.

64. HeoK, KimJS, KimK, KimH, ChoiJ, et al. (2012) Cell-penetrating H4 tail peptides potentiate p53-mediated transactivation via inhibition of G9a and HDAC1. Oncogene 32 : 2510–20.

65. GyoryI, WuJ, FejerG, SetoE, WrightKL (2004) PRDI-BF1 recruits the histone H3 methyltransferase G9a in transcriptional silencing. Nat Immunol 5 : 299–308.

66. SharifJ, EndohM, KosekiH (2011) Epigenetic memory meets G2/M: to remember or to forget? Dev Cell 20 : 5–6.

67. ZengX, ChenS, HuangH (2011) Phosphorylation of EZH2 by CDK1 and CDK2: a possible regulatory mechanism of transmission of the H3K27me3 epigenetic mark through cell divisions. Cell Cycle 10 : 579–583.

68. SmithE, HegaratN, VeselyC, RoseboomI, LarchC, et al. (2011) Differential control of Eg5-dependent centrosome separation by Plk1 and Cdk1. EMBO J 30 : 2233–2245.

69. WangXW, ZhanQ, CoursenJD, KhanMA, KontnyHU, et al. (1999) GADD45 induction of a G2/M cell cycle checkpoint. Proc Natl Acad Sci U S A 96 : 3706–3711.

70. VairapandiM, BallietAG, HoffmanB, LiebermannDA (2002) GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress. J Cell Physiol 192 : 327–338.

71. WatanabeN, MiiS, AsaiN, AsaiM, NiimiK, et al. (2013) The REV7 Subunit of DNA Polymerase zeta Is Essential for Primordial Germ Cell Maintenance in the Mouse. J Biol Chem 288 : 10459–10471.

72. LiuP, JenkinsNA, CopelandNG (2003) A highly efficient recombineering-based method for generating conditional knockout mutations. Genome Res 13 : 476–484.

73. 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.

74. PitulescuME, TeichmannM, LuoL, KesselM (2009) TIPT2 and geminin interact with basal transcription factors to synergize in transcriptional regulation. BMC Biochem 10 : 16.