Abstract
The multiple actions of estrogen in mammalian physiology are brought about, on a molecular level, by several signaling pathways, and mediated by at least two receptors-estrogen receptor (ER) α and β. Analysis of knock-out mice devoid of either or both receptor isoforms revealed the essential function of estrogen receptor α in female reproduction, as ERα deficiency leads to a complex endocrine phenotype, severe disturbances in several reproductive organs, and infertility. This reflects the many actions of estrogen in female reproductive endocrinology. To carry the understanding of estrogen action to a cellular resolution, modern genetic technologies can be employed, including artificial chromosome-based transgenesis and conditional gene targeting. The combination of these techniques yields mouse models that lack ERα in specific cell types of the body. Using cell-type-specific ERα mutants, it could be shown that ERα in neurons is essential for the luteinizing hormone (LH) surge that triggers ovulation. Studies using ERα and ERβ-selective agonists reveal that ERα activation is sufficient to induce an ovulatory hormonal stimulus. Thus, genetic analysis and selective pharmacological tools can complement each other in the molecular and cellular dissection of hormone receptor function in vivo.
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References
Abraham IM, Todman MG, Korach KS, Herbison AE (2004) Critical in vivo roles for classical estrogen receptors in rapid estrogen actions on intracellular signaling in mouse brain. Endocrinology 145:3055–3061
Beato M, Herrlich P, Schütz G (1995) Steroid hormone receptors: many actors in search of a plot. Cell 83:851–857
Blum A, Cannon ROI (1998) Effects of oestrogens and selective oestrogen receptor modulators on serum lipoproteins and vascular function. Curr Opin Lipidol 9:575–586
Bologa CG, Revankar CM, Young SM, Edwards BS, Arterburn JB, Kiselyov AS, Parker MA, Tkachenko SE, Savchuck NP, Sklar LA et al. (2006) Virtual and biomolecular screening converge on a selective agonist for GPRN30. Nat Chem Biol 2:207–212
Carlsten H (2005) Immune responses and bone loss: the estrogen connection. Immunol Rev 208:194–206
Casanova E, Fehsenfeld S, Mantamadiotis T, Lemberger T, Greiner E, Stewart AF, Schutz G (2001) A CamKIIalpha iCre BAC allows brain-specific gene inactivation. Genesis 31:37–42
Cole TJ, Blendy JA, Monaghan AP, Krieglstein K, Schmid W, Aguzzi A, Fantuzzi G, Hummler E, Unsicker K, Schutz G (1995) Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev 9:1608–1621
Couse JF, Korach KS (1999) Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev 20:358–417
Couse JF, Bunch DO, Lindzey J, Schomberg DW, Korach KS (1999) Prevention of the polycystic ovarian phenotype and characterization of ovulatory capacity in the estrogen receptor-α knockout mouse. Endocrinology 140:5855–5865
Couse JF, Yates MM, Walker VR, Korach KS (2003) Characterization of the hypothalamic-pituitary-gonadal axis in estrogen receptor (ER) null mice reveals hypergonadism and endocrine sex reversal in females lacking ERalpha but not ERbeta. Mol Endocrinol 17:1039–1053
Couse JF, Yates MM, Deroo BJ, Korach KS (2005) Estrogen receptor-{beta} is critical to granulosa cell differentiation and the ovulatory response to gonadotropins. Endocrinology 146:3244–3246
Daub H, Specht K, Ullrich A (2004) Strategies to overcome resistance to targeted protein kinase inhibitors. Nat Rev Drug Discov 3:1001–1010
Dorling AA, Todman MG, Korach KS, Herbison AE (2003) Critical role for estrogen receptor alpha in negative feedback regulation of gonadotropin-releasing hormone mRNA expression in the female mouse. Neuroendocrinology 78:204–209
Dubal DB, Zhu H, Yu J, Rau SW, Shughrue PJ, Merchenthaler I, Kindy MS, Wise PM (2001) Estrogen receptor alpha, not beta, is a critical link in estradiol-mediated protection against brain injury. Proc Natl Acad Sci USA 98:1952–1957
Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P, Mark M (2000) Effect of single and compound knockouts of estrogen receptors α (ERα) and β (ERβ) on mouse reproductive phenotypes. Development 127:4277–4291
Eddy EM, Washburn TF, Bunch DO, Goulding EH, Gladen BC, Lubahn DB, Korach KS (1996) Targeted disruption of the estrogen receptor gene in male mice causes alteration of spermatogenesis and infertility. Endocrinology 137:4796–4805
Emmen JM, Couse JF, Elmore SA, Yates MM, Kissling GE, Korach KS (2005) In vitro growth and ovulation of follicles from ovaries of estrogen receptor (ER)-{alpha} and ER{beta} null mice indicate a role for ER{beta} in follicular maturation. Endocrinology 146:2817–2826
Forster C, Makela S, Warri A, Kietz S, Becker D, Hultenby K, Warner M, Gustafsson JA (2002) Involvement of estrogen receptor beta in terminal differentiation of mammary gland epithelium. Proc Natl Acad Sci USA 99:15578–15583
Göttlicher M, Heck S, Herrlich P (1998) Transcriptional cross-talk, the second mode of steroid hormone receptor action. J Mol Med 76:480–489
Hall JM, Couse JF, Korach KS (2001) The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem 276:36869–36872
Harris HA, Albert LM, Leathurby Y, Malamas MS, Mewshaw RE, Miller CP, Kharode YP, Marzolf J, Komm BS, Winneker RC et al. (2003) Evaluation of an estrogen receptor-beta agonist in animal models of human disease. Endocrinology 144:4241–4249
Hegele-Hartung C, Siebel P, Peters O, Kosemund D, Muller G, Hillisch A, Walter A, Kraetzschmar J, Fritzemeier KH (2004) Impact of isotype-selective estrogen receptor agonists on ovarian function. Proc Natl Acad Sci USA 101:5129–5134
Herbison AE, Pape JR (2001) New evidence for estrogen receptors in gonadotropin-releasing hormone neurons. Front Neuroendocrinol 22:292–308
Hewitt SC, Korach KS (2003) Oestrogen receptor knockout mice: roles for oestrogen receptors alpha and beta in reproductive tissues. Reproduction 125:143–149
Hewitt SC, Harrell JC, Korach KS (2004) Lessons in estrogen biology from knockout and transgenic animals. Annu Rev Physiol 67:285–308
Hillisch A, Peters O, Kosemund D, Muller G, Walter A, Schneider B, Reddersen G, Elger W, Fritzemeier KH (2004) Dissecting physiological roles of estrogen receptor alpha and beta with potent selective ligands from structure-based design. Mol Endocrinol 18:1599–1609
Jones ME, Thorburn AW, Britt KL, Hewitt KN, Wreford NG, Proietto J, Oz OK, Leury BJ, Robertson KM, Yao S, Simpson ER (2000) Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci USA 97:12735–12740
Katzenellenbogen BS, Sun J, Harrington WR, Kraichely DM, Ganessunker D, Katzenellenbogen JA (2001) Structure-function relationships in estrogen receptors and the characterization of novel selective estrogen receptor modulators with unique pharmacological profiles. Ann NY Acad Sci 949:6–15
Kellendonk C, Opherk C, Anlag K, Schütz G, Tronche F (2000) Hepatocyte-specific expression of Cre recombinase. Genesis 26:151–153
Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, Sar M, Korach KS, Gustafsson J-A, Smithies O (1998) Generation and reproductive phenotypes of mice lacking estrogen receptor β. Proc Natl Acad Sci USA 95:15677–15682
Kuiper GG JM, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson J-A (1996) Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93:5925–5930
Lubahn D, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O (1993) Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci USA 90:11162–11166
Mendelsohn ME, Karas RH (1999) The protective effects of estrogen on the cardiovascular system. N Engl J Med 340:1801–1811
Mendelsohn ME, Karas RH (2001) The time has come to stop letting the HERS tale wag the dogma. Circulation 104:2256–2259
Mittelstadt PR, Ashwell JD (2003) Disruption of glucocorticoid receptor exon 2 yields a ligand-responsive C-terminal fragment that regulates gene expression. Mol Endocrinol 17:1534–1542
Mueller SO, Clark JA, Myers PH, Korach KS (2002) Mammary gland development in adult mice requires epithelial and stromal estrogen receptor alpha. Endocrinology 143:2357–2365
Nagy A (2000) Cre recombinase: the universal reagent for genome tailoring. Genesis 26:99–109
Ohlsson C, Hellberg N, Parini P, Vidal O, Bohlooly M, Rudling M, Lindberg MK, Warner M, Angelin B, Gustafsson J-A (2000) Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice. Biochem Biophys Res Commun 278:640–645
Pare G, Krust A, Karas RH, Dupont S, Aronovitz M, Chambon P, Mendelsohn ME (2002) Estrogen receptor-alpha mediates the protective effects of estrogen against vascular injury. Circ Res 90:1087–1092
Pendaries C, Darblade B, Rochaix P, Krust A, Chambon P, Korach KS, Bayard F, Arnal JF (2002) The AF-1 activation-function of ERalpha may be dispensable to mediate the effect of estradiol on endothelial NO production in mice. Proc Natl Acad Sci USA 99:2205–2210
Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER (2005) A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307:1625–1630
Simpson ER, Misso M, Hewitt KN, Hill RA, Boon WC, Jones ME, Kovacic A, Zhou J, Clyne CD (2005) Estrogen – the good, the bad, and the unexpected. Endocr Rev 26:322–330
Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, Orban PC, Bock R, Klein R, Schutz G (1999) Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat Genet 23:99–103
Turgeon JL, McDonnell DP, Martin KA, Wise PM (2004) Hormone therapy: physiological complexity belies therapeutic simplicity. Science 304:1269–1273
Valverde MA, Rojas P, Amigo J, Cosmelli D, Orio P, Bahamonde MI, Mann GE, Vergara C, Latorre R (1999) Acute activation of maxi-K channels (hSlo) by estradiol binding to the β subunit. Science 285:1929–1931
Van Amelsvoort T, Compton J, Murphy D (2001) In vivo assessment of the effects of estrogen on human brain. Trends Endocrinol Metab 12:273–276
Wintermantel TM, Berger S, Greiner EF, Schutz G (2004) Genetic dissection of corticosteroid receptor function in mice. Hormone Metab Res 36:387–391
Wintermantel TM, Campbell RE, Porteous R, Bock D, Gröne H-J, Todman MG, Korach KS, Greiner E, Perez CA, Schuetz G, Herbison AE (2006) Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility. Neuron 52:271–280
Zhu Y, Bian Z, Lu P, Karas RH, Bao L, Cox D, Hodgin J, Shaul PW, Thoren P, Smithies O et al. (2002) Abnormal vascular function and hypertension in mice deficient in estrogen receptor beta. Science 295:505–508
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Wintermantel, T.M., Elzer, J., Herbison, A.E., Fritzemeier, KH., Schütz, G. (2007). Genetic Dissection of Estrogen Receptor Signaling In Vivo. In: Korach, K.S., Wintermantel, T. (eds) Tissue-Specific Estrogen Action. Ernst Schering Foundation Symposium Proceedings, vol 2006/1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/2789_2006_015
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DOI: https://doi.org/10.1007/2789_2006_015
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