PDF herunterladen
Semin Reprod Med 2005; 23(1): 38-45
DOI: 10.1055/s-2005-864032
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Use of the Progesterone Receptor Antagonist RU 486 to Identify Novel Progesterone Receptor-Regulated Pathways in Implantation

Indrani C. Bagchi1 , Quanxi Li1 , Yong-Pil Cheon1 , Srinivasa Raju Mantena1 , Athilakshmi Kannan1 , Milan K. Bagchi1
  • 1Department of Veterinary Biosciences and Molecular & Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
15. Februar 2005 (online)

    Lizenzen und Reprints

ABSTRACT

The steroid hormone progesterone (P) is a critical regulator of embryo implantation and maintenance of pregnancy. P acting through the nuclear progesterone receptors (PRs) regulates the expression of specific gene networks that in turn control the extensive cell proliferation, differentiation, and remodeling that occur in various uterine cell types during the progressive phases of implantation. To identify the P-regulated pathways that underlie the implantation process in the mouse, we employed RU 486, a well-characterized PR antagonist that binds to the receptor and blocks its gene regulatory function. We performed messenger RNA (mRNA) profiling in the peri-implantation uterus using oligonucleotide microarrays to analyze changes in mRNA levels in response to RU 486. This analysis provided, for the first time, a comprehensive profile of PR-regulated gene networks with potential roles during implantation. Our study identified a variety of novel PR-regulated molecules, such as growth factors, protease inhibitors, metabolic enzymes, peptide hormones, transcription factors, immune response molecules, cytoskeletal proteins, and cell adhesion molecules, that are potential mediators of P action in the peri-implantation mouse uterus. This article provides a brief description of the expression and function of these newly identified molecular pathways.

KEYWORDS

Implantation - progesterone - receptor - antiprogestin RU 486

REFERENCES

  • 1 Psychoyos A. Endocrine control of egg implantation. In: Greep RO, Astwood EG Handbook of Physiology. Washington, DC; American Physiological Society 1973: 187-215
    Suche in Google Scholar
  • 2 Yoshinaga K. Uterine receptivity for blastocyst implantation.  Ann N Y Acad Sci. 1988;  541 424-431
    CrossrefPubMedSuche in Google Scholar
  • 3 Parr M B, Parr E L. The implantation reaction. In: Wynn RM, Jollie WP Biology of the Uterus. New York; Plenum Press 1989: 233-277
    Suche in Google Scholar
  • 4 Weitlauf H M. Biology of implantation. In: Knobil E, Neill JD The Physiology of Reproduction New York; Raven Press 1994: 391-440
    Suche in Google Scholar
  • 5 Carson D D, Bagchi I, Dey S K et al.. Embryo implantation (review).  Dev Biol. 2000;  223 217-237
    CrossrefPubMedSuche in Google Scholar
  • 6 Paria B C, Huet-Hudson Y M, Dey S K. Blastocyst's state of activity determines the “window” of implantation in the receptive mouse uterus.  Proc Natl Acad Sci USA. 1993;  90 10159-10162
    CrossrefPubMedSuche in Google Scholar
  • 7 Psychoyos A. Uterine receptivity for nidation.  Ann N Y Acad Sci. 1986;  476 36-42
    CrossrefPubMedSuche in Google Scholar
  • 8 Psychoyos A. Hormonal control of uterine receptivity for nidation.  J Reprod Fertil Suppl. 1976;  25 17-28
    PubMedSuche in Google Scholar
  • 9 Yoshinaga K. Inhibition of implantation by advancement of uterine sensitivity and refractoriness in blastocyst-endometrium relationships. In: Leroy F, Finn CA, Psychoyos A, Hubinot PO Progress in Reproductive Biology 7 Basel; Karger 1980: 189-199
  • 10 Finn C A. The implantation reaction. In: Wynn RM Biology of the Uterus. New York; Plenum Press 1977: 246-308
    Suche in Google Scholar
  • 11 De Feo V J. Decidualization. In: Wynn RM Cellular biology of the uterus. Amsterdam: North Holland; 1967: 191-290
    Suche in Google Scholar
  • 12 Cross J C, Werb Z, Fisher S J. Implantation and the placenta: key pieces of the developmental puzzle.  Science. 1994;  266 1508-1518
    CrossrefPubMedSuche in Google Scholar
  • 13 Irwin J C, Giudice L. Decidua. In: Knobil E, Neill JD Encyclopedia of Reproduction. Academic Press 1999: 823-835
    Suche in Google Scholar
  • 14 Gu Y, Gibori G. Deciduoma. In: Knobil E, Neill JD Encyclopedia of Reproduction. San Diego, CA; Academic Press 1999: 836-842
    Suche in Google Scholar
  • 15 Kirby D RS. The invasiveness of the trophoblast. In: Park W The early Conceptus, Normal and Abnormal University of St. Andrew Press 1965: 68-74
    Suche in Google Scholar
  • 16 Tsai M-J, O'Malley B W. Molecular mechanisms of action of steroid/thyroid receptor superfamily members.  Annu Rev Biochem. 1994;  63 451-486
    CrossrefPubMedSuche in Google Scholar
  • 17 Lydon J P, DeMayo F J, Funk C R et al.. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities.  Genes Dev. 1995;  9 2266-2278
    CrossrefPubMedSuche in Google Scholar
  • 18 Evans R M. The steroid and thyroid hormone receptor superfamily.  Science. 1988;  240 889-895
    CrossrefPubMedSuche in Google Scholar
  • 19 Mangelsdorf D J, Thummel C, Beato M et al.. The nuclear receptor superfamily: overview the second decade.  Cell. 1995;  83 835-839
    CrossrefPubMedSuche in Google Scholar
  • 20 Lessey B A. Two pathways of progesterone action in the human endometrium: implications for implantation and contraception.  Steroids. 2003;  68 809-815
    CrossrefPubMedSuche in Google Scholar
  • 21 Okulicz W C, Ace C I, Torres M S. Gene expression in the rhesus monkey endometrium: differential display and laser capture microdissection.  Front Biosci. 2003;  8 d551-d558
    PubMedSuche in Google Scholar
  • 22 Spencer T E, Bazer F W. Biology of progesterone action during pregnancy recognition and maintenance of pregnancy.  Front Biosci. 2002;  7 d1879-d1898
    CrossrefPubMedSuche in Google Scholar
  • 23 Rider V. Progesterone and the control of uterine cell proliferation and differentiation.  Front Biosci. 2002;  7 d1545-d1555
    PubMedSuche in Google Scholar
  • 24 Baulieu E E. Contragestion and other clinical applications of RU 486, an antiprogesterone at the receptor.  Science. 1989;  245 1351-1357
    CrossrefPubMedSuche in Google Scholar
  • 25 Baulieu E E. On the mechanism of action of RU 486.  Ann NY Acad Sci. 1991;  2 233-239
    PubMedSuche in Google Scholar
  • 26 Ding Y Q, Zhu L Z, Bagchi M K, Bagchi I C. Progesterone stimulates calcitonin gene expression in the uterus during implantation.  Endocrinology. 1994;  135 2265-2274
    CrossrefPubMedSuche in Google Scholar
  • 27 Cheon Y P, Li Q, DeMayo F J, Bagchi I C, Bagchi M K. A Genomic Approach to Identify Novel Progesterone Receptor Regulated Pathways in the Uterus during Implantation.  Mol Endocrinol. 2002;  16 2853-2871
    CrossrefPubMedSuche in Google Scholar
  • 28 Das S K, Chakraborty I, Paria B C, Wang X N, Plowman G, Dey S K. Amphiregulin is an implantation-specific and progesterone-regulated gene in the mouse uterus.  Mol Endocrinol. 1995;  9 691-705
    CrossrefPubMedSuche in Google Scholar
  • 29 Ma L, Benson G V, Lim H, Dey S K, Maas R L. Abdominal B(AbdB) Hoxa genes: regulation in adult uterus by estrogen and progesterone and repression in Mullerian duct by the synthetic estrogen diethylstilbestrol (DES).  Dev Biol. 1998;  197 141-154
    CrossrefPubMedSuche in Google Scholar
  • 30 Muffly K E, Jin D F, Okulicz W C, Kilpatrick D L. Gonadal steroids regulate proenkephalin gene expression in a tissue-specific manner within the female reproductive system.  Mol Endocrinol. 1988;  2 979-985
    PubMedSuche in Google Scholar
  • 31 Paria B C, Das N, Das S K, Zhao X, Dileepan K N, Dey S K. Histidine decarboxylase gene in the mouse uterus is regulated by progesterone and correlates with uterine differentiation for blastocyst implantation.  Endocrinology. 1998;  139 3958-3966
    CrossrefPubMedSuche in Google Scholar
  • 32 Martin L, Finn C A. Hormonal regulation of cell division in epithelial and connective tissues of mouse uterus.  J Endocrinol. 1968;  41 363-371
    PubMedSuche in Google Scholar
  • 33 Ducy P, Zhang R, Geoffroy V, Ridall A L, Kaesenty G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation.  Cell. 1997;  89 747-754
    CrossrefPubMedSuche in Google Scholar
  • 34 Enomoto H, Enomoto-Iwamoto M, Iwamoto M et al.. Cbfa1 is a positive regulatory factor in chondrocyte maturation.  J Biol Chem. 2000;  275 8695-8702
    CrossrefPubMedSuche in Google Scholar
  • 35 Luetteke N C, Qiu T H, Fenton S E et al.. Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development.  Development. 1999;  126 2739-2750
    PubMedSuche in Google Scholar
  • 36 Brigstock D R. The connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed (CCN) family.  Endocr Rev. 1999;  20 189-206
    CrossrefPubMedSuche in Google Scholar
  • 37 Babic A M, Chen C C, Lau L F. Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alpha v beta 3, promotes endothelial cell survival, and induces angiogenesis in vivo.  Mol Cell Biol. 1999;  19 2958-2966
    PubMedSuche in Google Scholar
  • 38 Zhu L-J, Bove K C, Polihronis M, Bagchi M K, Bagchi I C. Calcitonin is a progesterone-regulated marker which forecasts the receptive state of endometrium during implantation.  Endocrinology. 1998;  139 3923-3934
    CrossrefPubMedSuche in Google Scholar
  • 39 Rosen H, Itin A, Schiff R, Keshet E. Local regulation within the female reproductive system and upon embryonic implantation: identification of cells expressing proenkephalin A.  Mol Endocrinol. 1990;  4 146-154
    PubMedSuche in Google Scholar
  • 40 Manara L, Bianchetti A. The central and peripheral influences of opiods on gastrointestinal propulsion.  Annu Rev Pharmacol Toxicol. 1985;  25 249-273
    CrossrefPubMedSuche in Google Scholar
  • 41 Henderson G, North R A. Depression by morphine of excitatory junction potentials in the vas deferens of the mouse.  Br J Pharmacol. 1976;  57 341-346
    PubMedSuche in Google Scholar
  • 42 Zhu L Z, Bagchi M K, Bagchi I C. Attenuation of calcitonin gene expression in pregnant rat uterus leads to a block in embryonic implantation.  Endocrinology. 1998;  139 330-339
    CrossrefPubMedSuche in Google Scholar
  • 43 Li Q, Wang J, Armant D R, Bagchi M K, Bagchi I C. Calcitonin Down-Regulates E-cadherin Expression in Uterine Epithelium during Implantation.  J Biol Chem. 2002;  277 46447-46455
    CrossrefPubMedSuche in Google Scholar
  • 44 Li Q, Cheon Y P, Kannan A, Shanker S, Bagchi I C, Bagchi M K. A novel pathway involving progesterone receptor, 12/15-lipoxygenease-derived eicosanoids, and peroxisome proliferator-activated receptor γ? regulates implantation in mice.  J Biol Chem. 2004;  279 11570-11581
    CrossrefPubMedSuche in Google Scholar
  • 45 Mills J S, Needham M, Parker M G. A secretory protease inhibitor requires androgens for its expression in male sex accessory tissues but is expressed constitutively in pancreas.  EMBO J. 1987;  6 3711-3717
    PubMedSuche in Google Scholar
  • 46 Chen L Y, Lin Y H, Lai M L, Chen Y H. Developmental profile of a caltrin-like protease inhibitor, p12, in mouse seminal vesicle and characterization of its binding sites on sperm surface.  Biol Reprod. 1998;  59 1498-1505
    PubMedSuche in Google Scholar
  • 47 Delaria K, Fiorentino L, Wallace L, Tamburini P, Brownell E, Muller D. Inhibition of Cathepsin L-like Cysteine Proteases by Cytotoxic T-lymphocyte Antigen-2β.  J Biol Chem. 1994;  269 25172-25177
    PubMedSuche in Google Scholar
  • 48 Cheon Y P, Demayo F J, Bagchi M K, Bagchi I C. Induction of cytotoxic T-lymphocyte antigen-2 beta, a cysteine protease inhibitor in decidua: a potential regulator of embryo implantation.  J Biol Chem. 2004;  279 10357-10365
    PubMedSuche in Google Scholar
  • 49 Cheon Y P, Xu X, Bagchi M K, Bagchi I C. Immune-Responsive Gene 1 (Irg1) is a novel target of progesterone receptor and plays a critical role during implantation in the mouse.  Endocrinology. 2003;  144 5623-5630
    CrossrefPubMedSuche in Google Scholar
  • 50 Chen B, Zhang D, Pollard J W. Progesterone regulation of the mammalian ortholog of methylcitrate dehydratase (immune response gene 1) in the uterine epithelium during implantation through the protein kinase C pathway.  Mol Endocrinol. 2003;  17 2340-2354
    CrossrefPubMedSuche in Google Scholar
  • 51 Farnsworth R L, Talamantes F. Calcyclin in the mouse deciduas: expression and effects on placental lactogen secretion.  Biol Reprod. 1998;  59 546-552
    PubMedSuche in Google Scholar
  • 52 Meyer M E, Pornon A, Ji J, Bocquel M T, Chambon P, Gronemeyer H. Agonistic and antagonistic activities of RU486 on the functions of the human progesterone receptor.  EMBO J. 1990;  9 3923-3932
    PubMedSuche in Google Scholar
  • 53 Sartorius C A, Tung L, Takimoto G S, Horwitz K B. Antagonist-occupied human progesterone receptors bound to DNA are functionally switched to transcriptional agonists by cAMP.  J Biol Chem. 1993;  268 9262-9266
    PubMedSuche in Google Scholar
  • 54 Beck C A, Weigel N A, Moyer M L, Nordeen S K, Edwards D P. The progesterone antagonist RU486 acquires agonist activity upon stimulation of cAMP signaling pathways.  Proc Natl Acad Sci USA. 1993;  90 4441-4445
    PubMedSuche in Google Scholar
  • 55 Surveyor G A, Gendler S J, Pemberton L et al.. Expression and steroid hormonal control of Muc1 in the mouse uterus.  Endocrinology. 1995;  136 3639-3647
    CrossrefPubMedSuche in Google Scholar
  • 56 Teng C T, Pentiost B T, Chen Y M, Newbold R R, Eddy E M, McLachlan J A. Lactoferrin gene expression in the mouse uterus and mammary gland.  Endocrinology. 1989;  124 992-999
    PubMedSuche in Google Scholar
  • 57 McMaster M T, Teng C T, Dey S K, Andrews G K. Lactoferrin in the mouse uterus: analysis of the preimplantation period and regulation by ovarian steroids.  Mol Endocrinol. 1992;  6 101-111
    CrossrefPubMedSuche in Google Scholar

Indrani C Bagchi

Department of Veterinary Biosciences, University of Illinois at Urbana-Champaign

Urbana, IL 61802

eMail: ibagchi@uiuc.edu