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Endocrine Reviews 20 (3): 358-417
Copyright © 1999 by The Endocrine Society

Estrogen Receptor Null Mice: What Have We Learned and Where Will They Lead Us?

John F. Couse and Kenneth S. Korach

Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709

I. Introduction—A Historical Perspective
II. Estrogen Receptors (ER)
A. Gene and mRNA structure
B. Mechanism of ER action
C. Generation of the estrogen receptor null mice
III. Reproductive Tract Phenotypes of the Female
A. Uterus
B. Vagina
C. Oviduct
D. Ovary
IV. Mammary Gland
A. {alpha}ERKO phenotype
B. ßERKO phenotype
C. ER{alpha} and oncogene-induced tumorigenesis: Wnt-1/{alpha}ERKO mice
V. Reproductive Tract Phenotypes of the Male
A. Testicular function and spermatogenesis
B. Accessory sex organs
VI. Neuroendocrine System
A. Hypothalamic-pituitary axis
B. Behavior
VII. Phenotypes in Peripheral Tissues
A. Skeletal system
B. Cardiovascular system
C. Adipogenesis
VIII. Comparison with Human Disease and Models of Deficient Estrogen Action
A. Ovarian carcinogenesis
B. Chronic anovulation
C. ER{alpha} and aromatase deficiency
IX. Summary




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Physiol Rev, July 1, 2007; 87(3): 905 - 931.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
J. Miyamoto, T. Matsumoto, H. Shiina, K. Inoue, I. Takada, S. Ito, J. Itoh, T. Minematsu, T. Sato, T. Yanase, et al.
The Pituitary Function of Androgen Receptor Constitutes a Glucocorticoid Production Circuit
Mol. Cell. Biol., July 1, 2007; 27(13): 4807 - 4814.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
A. M. Trauernicht, S. J. Kim, N. H. Kim, and T. G. Boyer
Modulation of Estrogen Receptor {alpha} Protein Level and Survival Function by DBC-1
Mol. Endocrinol., July 1, 2007; 21(7): 1526 - 1536.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
J. Deschenes, V. Bourdeau, J. H. White, and S. Mader
Regulation of GREB1 Transcription by Estrogen Receptor {alpha} through a Multipartite Enhancer Spread Over 20 kb of Upstream Flanking Sequences
J. Biol. Chem., June 15, 2007; 282(24): 17335 - 17339.
[Abstract] [Full Text] [PDF]

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 Endocr Relat CancerHome page
F. Doll, J. Pfeilschifter, and A. Huwiler
Prolactin upregulates sphingosine kinase-1 expression and activity in the human breast cancer cell line MCF7 and triggers enhanced proliferation and migration
Endocr. Relat. Cancer, June 1, 2007; 14(2): 325 - 335.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
C. Glidewell-Kenney, L. A. Hurley, L. Pfaff, J. Weiss, J. E. Levine, and J. L. Jameson
Nonclassical estrogen receptor {alpha} signaling mediates negative feedback in the female mouse reproductive axis
PNAS, May 8, 2007; 104(19): 8173 - 8177.
[Abstract] [Full Text] [PDF]

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 ReproductionHome page
H O Goyal, T D Braden, P S Cooke, M A Szewczykowski, C S Williams, P Dalvi, and J W Williams
Estrogen receptor-{alpha} mediates estrogen-inducible abnormalities in the developing penis
Reproduction, May 1, 2007; 133(5): 1057 - 1067.
[Abstract] [Full Text] [PDF]

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 CarcinogenesisHome page
X. Peng, P. Jhaveri, E. A. Hussain-Hakimjee, and R. G. Mehta
Overexpression of ER and VDR is not sufficient to make ER-negative MDA-MB231 breast cancer cells responsive to 1{alpha}-hydroxyvitamin D5
Carcinogenesis, May 1, 2007; 28(5): 1000 - 1007.
[Abstract] [Full Text] [PDF]

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 J EndocrinolHome page
T. K S Ku and D. L Crowe
Coactivator-mediated estrogen response in human squamous cell carcinoma lines
J. Endocrinol., April 1, 2007; 193(1): 147 - 155.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
M. Lupien, M. Jeyakumar, E. Hebert, K. Hilmi, D. Cotnoir-White, C. Loch, A. Auger, G. Dayan, G.-A. Pinard, J.-M. Wurtz, et al.
Raloxifene and ICI182,780 Increase Estrogen Receptor-{alpha} Association with a Nuclear Compartment via Overlapping Sets of Hydrophobic Amino Acids in Activation Function 2 Helix 12
Mol. Endocrinol., April 1, 2007; 21(4): 797 - 816.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
A. S. Kauffman, M. L. Gottsch, J. Roa, A. C. Byquist, A. Crown, D. K. Clifton, G. E. Hoffman, R. A. Steiner, and M. Tena-Sempere
Sexual Differentiation of Kiss1 Gene Expression in the Brain of the Rat
Endocrinology, April 1, 2007; 148(4): 1774 - 1783.
[Abstract] [Full Text] [PDF]

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 Endocr Relat CancerHome page
P. Galluzzo, F. Caiazza, S. Moreno, and M. Marino
Role of ER{beta} palmitoylation in the inhibition of human colon cancer cell proliferation
Endocr. Relat. Cancer, March 1, 2007; 14(1): 153 - 167.
[Abstract] [Full Text] [PDF]

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 Adv. Physiol. Educ.Home page
M. E. Wierman
Sex steroid effects at target tissues: mechanisms of action
Advan Physiol Educ, March 1, 2007; 31(1): 26 - 33.
[Abstract] [Full Text] [PDF]

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 J. Neurosci.Home page
C. A. Christian and S. M. Moenter
Estradiol Induces Diurnal Shifts in GABA Transmission to Gonadotropin-Releasing Hormone Neurons to Provide a Neural Signal for Ovulation
J. Neurosci., February 21, 2007; 27(8): 1913 - 1921.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
H. A. Harris
Estrogen Receptor-{beta}: Recent Lessons from in Vivo Studies
Mol. Endocrinol., January 1, 2007; 21(1): 1 - 13.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
X. Fan, M. Warner, and J.-A. Gustafsson
Estrogen receptor beta expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons
PNAS, December 19, 2006; 103(51): 19338 - 19343.
[Abstract] [Full Text] [PDF]

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 J Mol EndocrinolHome page
M. Longo, B. Peruzzi, D. Fortunati, V. De Luca, S. Denger, G. Caselli, S. Migliaccio, and A. Teti
Modulation of human estrogen receptor {alpha} F promoter by a protein kinase C/c-Src-dependent mechanism in osteoblast-like cells
J. Mol. Endocrinol., December 1, 2006; 37(3): 489 - 502.
[Abstract] [Full Text] [PDF]

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 Pharmacol. Rev.Home page
P. Germain, B. Staels, C. Dacquet, M. Spedding, and V. Laudet
Overview of Nomenclature of Nuclear Receptors
Pharmacol. Rev., December 1, 2006; 58(4): 685 - 704.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
S. N. Sundar, V. Kerekatte, C. N. Equinozio, V. B. Doan, L. F. Bjeldanes, and G. L. Firestone
Indole-3-Carbinol Selectively Uncouples Expression and Activity of Estrogen Receptor Subtypes in Human Breast Cancer Cells
Mol. Endocrinol., December 1, 2006; 20(12): 3070 - 3082.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
P. Mussi, L. Liao, S.-E. Park, P. Ciana, A. Maggi, B. S. Katzenellenbogen, J. Xu, and B. W. O'Malley
Haploinsufficiency of the corepressor of estrogen receptor activity (REA) enhances estrogen receptor function in the mammary gland
PNAS, November 7, 2006; 103(45): 16716 - 16721.
[Abstract] [Full Text] [PDF]

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 J EndocrinolHome page
J. Lindzey, F. L Jayes, M. M Yates, J. F Couse, and K. S Korach
The bi-modal effects of estradiol on gonadotropin synthesis and secretion in female mice are dependent on estrogen receptor-{alpha}.
J. Endocrinol., October 1, 2006; 191(1): 309 - 317.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
J. E. O'Brien, T. J. Peterson, M. H. Tong, E.-J. Lee, L. E. Pfaff, S. C. Hewitt, K. S. Korach, J. Weiss, and J. L. Jameson
Estrogen-induced Proliferation of Uterine Epithelial Cells Is Independent of Estrogen Receptor {alpha} Binding to Classical Estrogen Response Elements
J. Biol. Chem., September 8, 2006; 281(36): 26683 - 26692.
[Abstract] [Full Text] [PDF]

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 J EndocrinolHome page
M J Meyer, A V Capuco, Y R Boisclair, and M E Van Amburgh
Estrogen-dependent responses of the mammary fat pad in prepubertal dairy heifers.
J. Endocrinol., September 1, 2006; 190(3): 819 - 827.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
S. Khan, R. Barhoumi, R. Burghardt, S. Liu, K. Kim, and S. Safe
Molecular Mechanism of Inhibitory Aryl Hydrocarbon Receptor--Estrogen Receptor/Sp1 Cross Talk in Breast Cancer Cells
Mol. Endocrinol., September 1, 2006; 20(9): 2199 - 2214.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
J. R. Schultz-Norton, W. H. McDonald, J. R. Yates, and A. M. Nardulli
Protein Disulfide Isomerase Serves as a Molecular Chaperone to Maintain Estrogen Receptor {alpha} Structure and Function
Mol. Endocrinol., September 1, 2006; 20(9): 1982 - 1995.
[Abstract] [Full Text] [PDF]

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 Hum Reprod UpdateHome page
K.R. Barnett, C. Schilling, C.R. Greenfeld, D. Tomic, and J.A. Flaws
Ovarian follicle development and transgenic mouse models
Hum. Reprod. Update, September 1, 2006; 12(5): 537 - 555.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
S. Ray, X. Hou, H.-E. Zhou, H. Wang, and S. K. Das
Bip Is a Molecular Link between the Phase I and Phase II Estrogenic Responses in Uterus
Mol. Endocrinol., August 1, 2006; 20(8): 1825 - 1837.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
J. F. Couse, M. M. Yates, K. F. Rodriguez, J. A. Johnson, D. Poirier, and K. S. Korach
The Intraovarian Actions of Estrogen Receptor-{alpha} Are Necessary to Repress the Formation of Morphological and Functional Leydig-Like Cells in the Female Gonad
Endocrinology, August 1, 2006; 147(8): 3666 - 3678.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
M. Y. Kim, E. M. Woo, Y. T. E. Chong, D. R. Homenko, and W. L. Kraus
Acetylation of Estrogen Receptor {alpha} by p300 at Lysines 266 and 268 Enhances the Deoxyribonucleic Acid Binding and Transactivation Activities of the Receptor
Mol. Endocrinol., July 1, 2006; 20(7): 1479 - 1493.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
R. W. Hsieh, S. S. Rajan, S. K. Sharma, Y. Guo, E. R. DeSombre, M. Mrksich, and G. L. Greene
Identification of Ligands with Bicyclic Scaffolds Provides Insights into Mechanisms of Estrogen Receptor Subtype Selectivity
J. Biol. Chem., June 30, 2006; 281(26): 17909 - 17919.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
Y. Yamamoto, R. Moore, H. A. Hess, G. L. Guo, F. J. Gonzalez, K. S. Korach, R. R. Maronpot, and M. Negishi
Estrogen Receptor {alpha} Mediates 17{alpha}-Ethynylestradiol Causing Hepatotoxicity
J. Biol. Chem., June 16, 2006; 281(24): 16625 - 16631.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
C. Le May, K. Chu, M. Hu, C. S. Ortega, E. R. Simpson, K. S. Korach, M.-J. Tsai, and F. Mauvais-Jarvis
Estrogens protect pancreatic beta-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice
PNAS, June 13, 2006; 103(24): 9232 - 9237.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
G. S. Daftary and H. S. Taylor
Endocrine Regulation of HOX Genes
Endocr. Rev., June 1, 2006; 27(4): 331 - 355.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
D. B. Dubal, S. W. Rau, P. J. Shughrue, H. Zhu, J. Yu, A. B. Cashion, S. Suzuki, L. M. Gerhold, M. B. Bottner, S. B. Dubal, et al.
Differential Modulation of Estrogen Receptors (ERs) in Ischemic Brain Injury: A Role for ER{alpha} in Estradiol-Mediated Protection against Delayed Cell Death
Endocrinology, June 1, 2006; 147(6): 3076 - 3084.
[Abstract] [Full Text] [PDF]


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