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Endocrine

, Volume 53, Issue 2, pp 595–606 | Cite as

MCM2 mediates progesterone-induced endometrial stromal cell proliferation and differentiation in mice

  • Shuangbo Kong
  • Xue Han
  • Tongtong Cui
  • Chan Zhou
  • Yufei Jiang
  • Hangxiao Zhang
  • Bingyan Wang
  • Haibin Wang
  • Shuang ZhangEmail author
Original Article

Abstract

Uterine decidualization characterized by stromal cell proliferation and differentiation is critical to the establishment of pregnancy in many species. Progesterone is a key factor in regulating endometrial cell decidualization, however, the molecular basis involved in mediating the effects of progesterone during decidualization remains largely unknown. We report here that the DNA replication licensing factor MCM2, one of the conserved set of six-related proteins (MCM complex: MCM2–7) essential for eukaryotic DNA replication, is dynamically expressed in both proliferative and differentiated stromal cells during mouse periimplantation uterus. Applying PR-knockout mouse model and pharmacological strategy, we further found that the expression of Mcm2 is induced by progesterone action in the mouse uterine stroma. Employing a primary cell culture system, we further demonstrated that siRNA-mediated silencing of MCM2 arrests the cell cycle at G1–S transition during stromal cell proliferation. Moreover, the downregulation of Mcm2 could also compromise stromal cell differentiation. Collectively, our studies uncovered the role of a unique DNA replication licensing molecule MCM2 in mediating Progesterone-induced stromal cell decidualization in mouse uterus.

Keywords

Mcm2 Uterine stroma Decidualization S-phase Progesterone 

Notes

Acknowledgments

This work was supported in parts by the National Basic Research Program of China (2011CB944400 to H.W.) and the National Natural Science Foundation (81130009 and 81330017 to H.W. and to 31471106 to S.Z.).

Compliance with ethical standards

Conflict of interest

The authors declared that they have no conflict of interests.

Supplementary material

12020_2016_894_MOESM1_ESM.docx (375 kb)
Supplementary material 1 (DOCX 375 kb)

References

  1. 1.
    H. Wang, S.K. Dey, Roadmap to embryo implantation: clues from mouse models. Nat. Rev. Genet. 7, 185–199 (2006)CrossRefPubMedGoogle Scholar
  2. 2.
    S.K. Dey, Focus on implantation. Reproduction 128, 655–656 (2004)CrossRefPubMedGoogle Scholar
  3. 3.
    M.J. Large, F.J. DeMayo, The regulation of embryo implantation and endometrial decidualization by progesterone receptor signaling. Mol. Cell Endocrinol. 358, 155–165 (2012)CrossRefPubMedGoogle Scholar
  4. 4.
    J. Cha, X. Sun, S.K. Dey, Mechanisms of implantation: strategies for successful pregnancy. Nat. Med. 18, 1754–1767 (2012)CrossRefPubMedGoogle Scholar
  5. 5.
    O.M. Conneely et al., Reproductive functions of progesterone receptors. Recent Prog. Horm. Res. 57, 339–355 (2002)CrossRefPubMedGoogle Scholar
  6. 6.
    S.K. Das, Cell cycle regulatory control for uterine stromal cell decidualization in implantation. Reproduction 137, 889–899 (2009)CrossRefPubMedGoogle Scholar
  7. 7.
    S. Zhang et al., Deciphering the molecular basis of uterine receptivity. Mol. Reprod. Dev. 80, 8–21 (2013)CrossRefPubMedGoogle Scholar
  8. 8.
    S.K. Das et al., Cyclin D3 in the mouse uterus is associated with the decidualization process during early pregnancy. J. Mol. Endocrinol. 22, 91–101 (1999)CrossRefPubMedGoogle Scholar
  9. 9.
    J.M. Sroga et al., Overexpression of cyclin D3 improves decidualization defects in Hoxa-10(−/−) mice. Endocrinology 153, 5575–5586 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    P. Bilinski, D. Roopenian, A. Gossler, Maternal IL-11Ralpha function is required for normal decidua and fetoplacental development in mice. Genes Dev. 12, 2234–2243 (1998)CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    M. Mori et al., Death effector domain-containing protein (DEDD) is required for uterine decidualization during early pregnancy in mice. J. Clin. Investig. 121, 318–327 (2011)CrossRefPubMedGoogle Scholar
  12. 12.
    J.J. Blow, A. Dutta, Preventing re-replication of chromosomal DNA. Nat. Rev. Mol. Cell Biol. 6, 476–486 (2005)CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    M. Moritani, Y. Ishimi, Inhibition of DNA binding of MCM2-7 complex by phosphorylation with cyclin-dependent kinases. J. Biochem. 154, 363–372 (2013)CrossRefPubMedGoogle Scholar
  14. 14.
    L.C. Chuang et al., Phosphorylation of Mcm2 by Cdc7 promotes pre-replication complex assembly during cell-cycle re-entry. Mol. Cell 35, 206–216 (2009)CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Q. Wei et al., Phosphorylation of minichromosome maintenance protein 7 (MCM7) by cyclin/cyclin-dependent kinase affects its function in cell cycle regulation. J. Biol. Chem. 288, 19715–19725 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    H. Pan, Y. Deng, J.W. Pollard, Progesterone blocks estrogen-induced DNA synthesis through the inhibition of replication licensing. Proc. Natl. Acad. Sci. USA 103, 14021–14026 (2006)CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    S. Ray, J.W. Pollard, KLF15 negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication licensing. Proc. Natl. Acad. Sci. USA 109, E1334–E1343 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    J.P. Lydon et al., Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 9, 2266–2278 (1995)CrossRefPubMedGoogle Scholar
  19. 19.
    G.A. Surveyor et al., Expression and steroid hormonal control of Muc-1 in the mouse uterus. Endocrinology 136, 3639–3647 (1995)PubMedGoogle Scholar
  20. 20.
    Q. Wang et al., Wnt6 is essential for stromal cell proliferation during decidualization in mice. Biol. Reprod. 88, 5 (2013)CrossRefPubMedGoogle Scholar
  21. 21.
    J. Lu et al., A positive feedback loop involving Gcm1 and Fzd5 directs chorionic branching morphogenesis in the placenta. PLoS Biol. 11, e1001536 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    S. Zhang et al., Uterine Rbpj is required for embryonic-uterine orientation and decidual remodeling via Notch pathway-independent and -dependent mechanisms. Cell Res. 24, 925–942 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    B.J. Plante et al., Cyclic regulation of transcription factor C/EBP beta in human endometrium. Reprod. Biol. Endocrinol. 7, 15 (2009)CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Q. Li et al., Bone morphogenetic protein 2 functions via a conserved signaling pathway involving Wnt4 to regulate uterine decidualization in the mouse and the human. J. Biol. Chem. 282, 31725–31732 (2007)CrossRefPubMedGoogle Scholar
  25. 25.
    L. Loeb, The production of Deciduomata. JAMA 50, 1897 (1908)CrossRefGoogle Scholar
  26. 26.
    B.C. Paria et al., Uterine decidual response occurs in estrogen receptor-alpha-deficient mice. Endocrinology 140, 2704–2710 (1999)PubMedPubMedCentralGoogle Scholar
  27. 27.
    A. Das et al., De novo synthesis of estrogen in pregnant uterus is critical for stromal decidualization and angiogenesis. Proc. Natl. Acad. Sci. USA 106, 12542–12547 (2009)CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    S.W. Curtis et al., Disruption of estrogen signaling does not prevent progesterone action in the estrogen receptor alpha knockout mouse uterus. Proc. Natl. Acad. Sci. USA 96, 3646–3651 (1999)CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    S.A. Mani et al., The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008)CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    S.R. Glasser, J. Julian, Intermediate filament protein as a marker of uterine stromal cell decidualization. Biol. Reprod. 35, 463–474 (1986)CrossRefPubMedGoogle Scholar
  31. 31.
    J. Tan et al., Evidence for coordinated interaction of cyclin D3 with p21 and cdk6 in directing the development of uterine stromal cell decidualization and polyploidy during implantation. Mech. Dev. 111, 99–113 (2002)CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    P.S. Cooke et al., Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium. Proc. Natl. Acad. Sci. USA 94, 6535–6540 (1997)CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    L. Zhu, J.W. Pollard, Estradiol-17beta regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling. Proc. Natl. Acad. Sci. USA 104, 15847–15851 (2007)CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    W. Winuthayanon et al., Uterine epithelial estrogen receptor alpha is dispensable for proliferation but essential for complete biological and biochemical responses. Proc. Natl. Acad. Sci. USA 107, 19272–19277 (2010)CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    T. Kurita et al., Stromal progesterone receptors mediate the inhibitory effects of progesterone on estrogen-induced uterine epithelial cell deoxyribonucleic acid synthesis. Endocrinology 139, 4708–4713 (1998)PubMedGoogle Scholar
  36. 36.
    H.L. Franco et al., Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function. FASEB J. 26, 1218–1227 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    S. Suzuki et al., Overexpression of MCM2 in myelodysplastic syndromes: association with bone marrow cell apoptosis and peripheral cytopenia. Exp. Mol. Pathol. 92, 160–166 (2012)CrossRefPubMedGoogle Scholar
  38. 38.
    K.M. Barton, E.M. Levine, Expression patterns and cell cycle profiles of PCNA, MCM6, cyclin D1, cyclin A2, cyclin B1, and phosphorylated histone H3 in the developing mouse retina. Dev. Dyn. 237, 672–682 (2008)CrossRefPubMedGoogle Scholar
  39. 39.
    S.S. Li et al., Replicative MCM7 protein as a proliferation marker in endometrial carcinoma: a tissue microarray and clinicopathological analysis. Histopathology 46, 307–313 (2005)CrossRefPubMedGoogle Scholar
  40. 40.
    J.M. Bailis, S.L. Forsburg, MCM proteins: DNA damage, mutagenesis and repair. Curr. Opin. Genet. Dev. 14, 17–21 (2004)CrossRefPubMedGoogle Scholar
  41. 41.
    K. Kato et al., Expression of replication-licensing factors MCM2 and MCM3 in normal, hyperplastic, and carcinomatous endometrium: correlation with expression of Ki-67 and estrogen and progesterone receptors. Int. J. Gynecol. Pathol. 22, 334–340 (2003)CrossRefPubMedGoogle Scholar
  42. 42.
    A. Ibarra, E. Schwob, J. Mendez, Excess MCM proteins protect human cells from replicative stress by licensing backup origins of replication. Proc. Natl. Acad. Sci. USA 105, 8956–8961 (2008)CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    X.Q. Ge, D.A. Jackson, J.J. Blow, Dormant origins licensed by excess Mcm2-7 are required for human cells to survive replicative stress. Genes Dev. 21, 3331–3341 (2007)CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    O.D. Slayden et al., Chronic treatment of cycling rhesus monkeys with low doses of the antiprogestin ZK 137 316: morphometric assessment of the uterus and oviduct. Hum. Reprod. 13, 269–277 (1998)CrossRefPubMedGoogle Scholar
  45. 45.
    O. Heikinheimo et al., Endometrial effects of RU486 in primates–antiproliferative action despite signs of estrogen action and increased cyclin-B expression. J. Steroid Biochem. Mol. Biol. 59, 179–190 (1996)CrossRefPubMedGoogle Scholar
  46. 46.
    C.A. Rubel et al., Research resource: genome-wide profiling of progesterone receptor binding in the mouse uterus. Mol. Endocrinol. 26, 1428–1442 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    J.M. Sroga, X. Ma, S.K. Das, Developmental regulation of decidual cell polyploidy at the site of implantation. Front. Biosci. (Sch. Ed.). 4, 1475–1486 (2012)Google Scholar
  48. 48.
    D.D. Carson, Embryo implantation: molecular, cellular and clinical aspects (Springer Science & Business Media, New York, 2013)Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Shuangbo Kong
    • 1
  • Xue Han
    • 1
  • Tongtong Cui
    • 1
  • Chan Zhou
    • 1
  • Yufei Jiang
    • 1
  • Hangxiao Zhang
    • 1
  • Bingyan Wang
    • 1
  • Haibin Wang
    • 1
  • Shuang Zhang
    • 1
    Email author
  1. 1.State Key Laboratory of Reproductive Biology, Institute of ZoologyChinese Academy of SciencesBeijingPeople’s Republic of China

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