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.
Similar content being viewed by others
References
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Schibler U, Sassone-Corsi P (2002) A web of circadian pacemakers. Cell 111:919–922. doi:10.1016/S0092-8674(02)01225-4
Akashi M, Nishida E (2000) Involvement of the MAP kinase cascade in resetting of the mammalian circadian clock. Genes Dev 14:645–649
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
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
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
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
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
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
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
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
Morin LP, Fitzgerald KM, Zucker I (1977) Estradiol shortens the period of hamster circadian rhythms. Science 196:305–307. doi:10.1126/science.557840
Thomas EM, Armstrong SM (1989) Effect of ovariectomy and estradiol on unity of female rat circadian rhythms. Am J Physiol 257:R1241–R1250
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
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
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
Psychoyos A (1986) Uterine receptivity for nidation. Ann N Y Acad Sci 476:36–42. doi:10.1111/j.1749-6632.1986.tb20920.x
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
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
Clarke CL, Sutherland RL (1990) Progestin regulation of cellular proliferation. Endocr Rev 11:266–301
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Corresponding author
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-008-9981-4