Skip to main content
Log in

Progesterone, but not estradiol, synchronizes circadian oscillator in the uterus endometrial stromal cells

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The circadian oscillator is generated within the suprachiasmatic nuclei and synchronizes circadian clocks in numerous peripheral tissues. The molecular basis is composed of a number of genes and proteins that form transcriptional and translational feedback loops. Such molecular oscillators are also operative in peripheral tissues, including in the uterus. Although ovarian steroids regulate the function of uterine endometrial stromal cells, the modulation of ovarian steroids on the circadian rhythms remains unknown. Here we investigate the possibility that estradiol (E2) and progesterone (P4) modulate the circadian oscillator of the stromal cells. The study using transgenic rats constructed with Period 2 (Per2) promoter-destabilized luciferase (Per2-dLuc) gene, with the real-time monitoring system of Per2-dLuc oscillation. The stromal cells displayed constant Per2-dLuc oscillation after treatment with dexamethasone, suggesting that the circadian oscillator is operative. However, the circadian oscillator was disrupted by in vivo administration of human chorionic gonadotropin (hCG) following equine chorionic gonadotropin (eCG), although it was altered into a rhythmic pattern 4 days later following hCG. Chronic treatment with P4 induced constant Per2-dLuc oscillation in the stromal cells from eCG-treated immature and pregnant rats, whereas E2 did not promote such a rhythmic Per2-dLuc oscillation. Collectively, P4 synchronizes the circadian oscillator of the uterus endometrial stromal cells through transcriptional and translational feedback loops of the clockwork system.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Reppert SM, Weaver DR (2001) Molecular analysis of mammalian circadian rhythms. Annu Rev Physiol 63:647–676. doi:10.1146/annurev.physiol.63.1.647

    Article  PubMed  CAS  Google Scholar 

  2. Shearman LP, Sriram S, Weaver DR, Maywood ES, Chaves I, Zheng B, Kume K, Lee CC, van der Horst GT, Hastings MH, Reppert SM (2000) Interacting molecular loops in the mammalian circadian clock. Science 288:1013–1019. doi:10.1126/science.288.5468.1013

    Article  PubMed  CAS  Google Scholar 

  3. Ueda HR, Hayashi S, Chen W, Sano M, Machida M, Shigeyoshi Y, Iino M, Hashimoto S (2005) System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat Genet 37:187–192. doi:10.1038/ng1504

    Article  PubMed  CAS  Google Scholar 

  4. Yamamoto T, Nakahata Y, Soma H, Akashi M, Mamine T, Takumi T (2004) Transcriptional oscillation of canonical clock genes in mouse peripheral tissues. BMC Mol Biol 5:18. doi:10.1186/1471-2199-5-18

    Article  PubMed  CAS  Google Scholar 

  5. Lemos DR, Downs JL, Urbanski HF (2006) Twenty-four-hour rhythmic gene expression in the rhesus macaque adrenal gland. Mol Endocrinol 20:1164–1176. doi:10.1210/me.2005-0361

    Article  PubMed  CAS  Google Scholar 

  6. Nakamura TJ, Moriya T, Inoue S, Shimazoe T, Watanabe S, Ebihara S, Shinohara K (2005) Estrogen differentially regulates expression of Per1 and Per2 genes between central and peripheral clocks and between reproductive and nonreproductive tissues in female rats. J Neurosci Res 82:622–630. doi:10.1002/jnr.20677

    Article  PubMed  CAS  Google Scholar 

  7. Dolatshad H, Campbell EA, O’Hara L, Maywood ES, Hastings MH, Johnson MH (2006) Developmental and reproductive performance in circadian mutant mice. Hum Reprod 21:68–79. doi:10.1093/humrep/dei313

    Article  PubMed  CAS  Google Scholar 

  8. He P-J, Hirata M, Yamauchi N, Hattori M-A (2007) Up-regulation of Per1 expression by estradiol and progesterone in the rat uterus. J Endocrinol 194:511–519. doi:10.1677/JOE-07-0172

    Article  PubMed  CAS  Google Scholar 

  9. Morse D, Cermakian N, Brancorsini S, Parvinen M, Sassone-Corsi P (2003) No circadian rhythms in testis: Period1 expression is clock independent and developmentally regulated in the mouse. Mol Endocrinol 17:141–151. doi:10.1210/me.2002-0184

    Article  PubMed  CAS  Google Scholar 

  10. Alvarez JD, Chen D, Storer E, Sehgal A (2003) Non-cyclic and developmental stage-specific expression of circadian clock proteins during murine spermatogenesis. Biol Reprod 69:81–91. doi:10.1095/biolreprod.102.011833

    Article  PubMed  CAS  Google Scholar 

  11. Alvarez JD, Sehgal A (2005) The thymus is similar to the testis in its pattern of circadian clock gene expression. J Biol Rhythms 20:111–121. doi:10.1177/0748730404274078

    Article  PubMed  CAS  Google Scholar 

  12. He PJ, Hirata M, Yamauchi N, Hashimoto S, Hattori M-A (2007) The disruption of circadian clockwork in differentiating cells from rat reproductive tissues as identified by in vitro real-time monitoring system. J Endocrinol 193:413–420. doi:10.1677/JOE-07-0044

    Article  PubMed  CAS  Google Scholar 

  13. He PJ, Hirata M, Yamauchi N, Hashimoto S, Hattori M-A (2007) Gonadotropic regulation of circadian clockwork in rat granulosa cells. Mol Cell Biochem 302:111–118. doi:10.1007/s11010-007-9432-7

    Article  PubMed  CAS  Google Scholar 

  14. Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury-Olela F, Schibler U (2000) Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev 14:2950–2961. doi:10.1101/gad.183500

    Article  PubMed  CAS  Google Scholar 

  15. Schibler U, Sassone-Corsi P (2002) A web of circadian pacemakers. Cell 111:919–922. doi:10.1016/S0092-8674(02)01225-4

    Article  PubMed  CAS  Google Scholar 

  16. Akashi M, Nishida E (2000) Involvement of the MAP kinase cascade in resetting of the mammalian circadian clock. Genes Dev 14:645–649

    PubMed  CAS  Google Scholar 

  17. Balsalobre A, Brown SA, Marcacci L, Tronche F, Kellendonk C, Reichardt HM, Schutz G, Schibler U (2000) Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 289:2344–2347. doi:10.1126/science.289.5488.2344

    Article  PubMed  CAS  Google Scholar 

  18. Balsalobre A, Marcacci L, Schibler U (2000) Multiple signaling pathways elicit circadian gene expression in cultured Rat-1 fibroblasts. Curr Biol 10:1291–1294. doi:10.1016/S0960-9822(00)00758-2

    Article  PubMed  CAS  Google Scholar 

  19. Tsuchiya Y, Minami I, Kadotani H, Nishida E (2005) Resetting of peripheral circadian clock by prostaglandin E2. EMBO Rep 6:256–261. doi:10.1038/sj.embor.7400356

    Article  PubMed  CAS  Google Scholar 

  20. Hinoi E, Ueshima T, Hojo H, Iemata M, Takarada T, Yoneda Y (2006) Up-regulation of per mRNA expression by parathyroid hormone through a protein kinase A-CREB-dependent mechanism in chondrocytes. J Biol Chem 281:23632–23642. doi:10.1074/jbc.M512362200

    Article  PubMed  CAS  Google Scholar 

  21. Nakahata Y, Akashi M, Trcka D, Yasuda A, Takumi T (2006) The in vitro real-time oscillation monitoring system identifies potential entrainment factors for circadian clocks. BMC Mol Biol 7:5. doi:10.1186/1471-2199-7-5

    Article  PubMed  CAS  Google Scholar 

  22. Shirai H, Oishi K, Ishida N (2006) Circadian expression of clock genes is maintained in the liver of Vitamin A-deficient mice. Neurosci Lett 398:69–72. doi:10.1016/j.neulet.2005.12.055

    Article  PubMed  CAS  Google Scholar 

  23. Low-Zeddies SS, Takahashi JS (2001) Chimera analysis of the clock mutation in mice shows that complex cellular integration determines circadian behavior. Cell 105:25–42. doi:10.1016/S0092-8674(01)00294-X

    Article  PubMed  CAS  Google Scholar 

  24. Miller BH, Olson SL, Turek FW, Levine JE, Horton TH, Takahashi JS (2004) Circadian clock mutation disrupts estrous cyclicity and maintenance of pregnancy. Curr Biol 14:1367–1373. doi:10.1016/j.cub.2004.07.055

    Article  PubMed  CAS  Google Scholar 

  25. Morin LP, Fitzgerald KM, Zucker I (1977) Estradiol shortens the period of hamster circadian rhythms. Science 196:305–307. doi:10.1126/science.557840

    Article  PubMed  CAS  Google Scholar 

  26. Thomas EM, Armstrong SM (1989) Effect of ovariectomy and estradiol on unity of female rat circadian rhythms. Am J Physiol 257:R1241–R1250

    PubMed  CAS  Google Scholar 

  27. Perrin JS, Segall LA, Harbour VL, Woodside B, Amir S (2006) The expression of the clock protein PER2 in the limbic forebrain is modulated by the estrous cycle. Proc Natl Acad Sci USA 103:5591–5596. doi:10.1073/pnas.0601310103

    Article  PubMed  CAS  Google Scholar 

  28. Axelson JF, Zoller LC, Tomassone JE, Collins DC (1986) Effects of silastic progesterone implants on activity cycles and steroid levels in ovariectomized and intact female rats. Physiol Behav 38:879–885. doi:10.1016/0031-9384(86)90057-0

    Article  PubMed  CAS  Google Scholar 

  29. Labyak SE, Lee TM (1995) Estrus- and steroid-induced changes in circadian rhythms in a diurnal rodent, octodon degus. Physiol Behav 58:573–585. doi:10.1016/0031-9384(95)00096-2

    Article  PubMed  CAS  Google Scholar 

  30. Psychoyos A (1986) Uterine receptivity for nidation. Ann N Y Acad Sci 476:36–42. doi:10.1111/j.1749-6632.1986.tb20920.x

    Article  PubMed  CAS  Google Scholar 

  31. Yoshinaga K (1988) Uterine receptivity for blastocyst implantation. Ann N Y Acad Sci 541:424–431. doi:10.1111/j.1749-6632.1988.tb22279.x

    Article  PubMed  CAS  Google Scholar 

  32. Carson DD, Bagchi I, Dey SK, Enders AC, Fazleabas AT, Lessey BA, Yoshinaga K (2000) Embryo implantation. Dev Biol 223:217–237. doi:10.1006/dbio.2000.9767

    Article  PubMed  CAS  Google Scholar 

  33. Clarke CL, Sutherland RL (1990) Progestin regulation of cellular proliferation. Endocr Rev 11:266–301

    Article  PubMed  CAS  Google Scholar 

  34. Zhang Z, Funk C, Glasser SR, Mulholland J (1994) Progesterone regulation of heparin-binding epidermal growth factor-like growth factor gene expression during sensitization and decidualization in the rat uterus: effects of antiprogestins, ZK 98.299. Endocrinology 135:1256–1263. doi:10.1210/en.135.3.1256

    Article  PubMed  CAS  Google Scholar 

  35. Ueda HR, Chen W, Adachi A, Wakamatsu H, Hayashi S, Takasugi T, Nagano M, Nakahama K, Suzuki Y, Sugano S, Iino M, Shigeyoshi Y, Hashimoto S (2002) A transcription factor response element for gene expression during circadian night. Nature 418:534–539. doi:10.1038/nature00906

    Article  PubMed  CAS  Google Scholar 

  36. Travnickova-Bendova Z, Cermakian N, Reppert SM, Sassone-Corsi P (2002) Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity. Proc Natl Acad Sci USA 99:7728–7733. doi:10.1073/pnas.102075599

    Article  PubMed  CAS  Google Scholar 

  37. Weihua Z, Saji S, Makinen S, Cheng G, Jensen EV, Warner M, Gustafsson JA (2000) Estrogen receptor (ERβ), a modulator of ERα in the uterus. Proc Natl Acad Sci USA 97:5936–5941. doi:10.1073/pnas.97.11.5936

    Article  PubMed  CAS  Google Scholar 

  38. Chen B, Pan H, Zhu L, Deng Y, Pollard JW (2005) Progesterone inhibits the estrogen-induced phosphoinositide 3-kinase->AKT->GSK-3β->Cyclin D1->pRB pathway to block uterine epithelial cell proliferation. Mol Endocrinol 19:1978–1990. doi:10.1210/me.2004-0274

    Article  PubMed  CAS  Google Scholar 

  39. Darlington TK, Wager-Smith K, Ceriani MJ, Staknis D, Gekakis N, Steeves TDL, Weitz CJ, Takahashi JS, Kay SA (1998) Closing the circadian loop: CLOCK-induced transcription of its own inhibitors per and tim. Science 280:1599–1603. doi:10.1126/science.280.5369.1599

    Article  PubMed  CAS  Google Scholar 

  40. Bagchi MK, Elliston JF, Tsai SY, Edwards DP, Tsai MJ, O’Malley BW (1988) Steroid hormone-dependent interaction of human progesterone receptor with its target enhancer element. Mol Endocrinol 2:1221–1229

    Article  PubMed  CAS  Google Scholar 

  41. Anderson I, Gorski J (2000) Estrogen receptor α interaction with estrogen response element half-sites from the rat prolactin gene. Biochemistry 39:3842–3847. doi:10.1021/bi9924516

    Article  PubMed  CAS  Google Scholar 

  42. Edwards DP (2005) Regulation of signal transduction pathways by estrogen and progesterone. Annu Rev Physiol 67:335–376. doi:10.1146/annurev.physiol.67.040403.120151

    Article  PubMed  CAS  Google Scholar 

  43. Yoo S-H, Ko CH, Lowrey PL, Buhr ED, Song E, Chang S, Yoo OJ, Yamazaki S, Lee C, Takahashi JS (2005) A noncanonical E-box enhancer drives mouse Period2 circadian oscillations in vivo. Proc Natl Acad Sci USA 102:2608–2613. doi:10.1073/pnas.0409763102

    Article  PubMed  CAS  Google Scholar 

  44. Akashi M, Ichise T, Mamine T, Takumi T (2006) Molecular mechanism of cell-autonomous circadian gene expression of Period2, a crucial regulator of the mammalian circadian clock. Mol Biol Cell 17:555–565. doi:10.1091/mbc.E05-05-0396

    Article  PubMed  CAS  Google Scholar 

  45. Gery S, Virk RK, Chumakov K, Yu A, Koeffler HP (2007) The clock gene Per2 links the circadian system to the estrogen receptor. Oncogene 26:7916–7920. doi:10.1038/sj.onc.1210585

    Article  PubMed  CAS  Google Scholar 

  46. Cheon Y-P, Li Q, Xu X, DeMayo FJ, Bagchi IC, Bagchi MK (2002) A genomic approach to identify novel progesterone receptor regulated pathways in the uterus during implantation. Mol Endocrinol 16:2853–2871. doi:10.1210/me.2002-0270

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to Christopher Wood (Zhejiang University) for his critical reading of the manuscript. This research was supported in part by a Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Sciences (JSPS; 16380200) (to M-A H).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Masa-aki Hattori.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hirata, M., He, PJ., Shibuya, N. et al. Progesterone, but not estradiol, synchronizes circadian oscillator in the uterus endometrial stromal cells. Mol Cell Biochem 324, 31–38 (2009). https://doi.org/10.1007/s11010-008-9981-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-008-9981-4

Keywords

Navigation