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Science 286 (5448): 2328-2331

Copyright © 1999 by the American Association for the Advancement of Science

Postnatal Sex Reversal of the Ovaries in Mice Lacking Estrogen Receptors alpha  and beta  

J. F. Couse, 1 S. Curtis Hewitt, 1 D. O. Bunch, 2 M. Sar, 3 V. R. Walker, 1 B. J. Davis, 4 K. S. Korach 1*

Mice lacking estrogen receptors alpha  and beta  were generated to clarify the roles of each receptor in the physiology of estrogen target tissues. Both sexes of alpha beta estrogen receptor knockout (alpha beta ERKO) mutants exhibit normal reproductive tract development but are infertile. Ovaries of adult alpha beta ERKO females exhibit follicle transdifferentiation to structures resembling seminiferous tubules of the testis, including Sertoli-like cells and expression of Müllerian inhibiting substance, sulfated glycoprotein-2, and Sox9. Therefore, loss of both receptors leads to an ovarian phenotype that is distinct from that of the individual ERKO mutants, which indicates that both receptors are required for the maintenance of germ and somatic cells in the postnatal ovary.

1 Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology,
4 Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
2 Laboratory of Reproductive Biology, Department of Cell Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
3 Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709, USA.
*   To whom correspondence should be addressed. E-mail: korach{at}niehs.nih.gov


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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »
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P. T.K. Saunders, R. M. Sharpe, K. Williams, S. Macpherson, H. Urquart, D.S. Irvine, and M. R. Millar (2001)
Mol. Hum. Reprod. 7, 227-236
   Abstract »    Full Text »    PDF »
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   Abstract »    PDF »
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   Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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S. Nef and L. F. Parada (2000)
Genes & Dev. 14, 3075-3086
   Full Text »
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   Abstract »    Full Text »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »
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   Abstract »    Full Text »    PDF »
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S Dupont, A Krust, A Gansmuller, A Dierich, P Chambon, and M Mark (2000)
Development 127, 4277-4291
   Abstract »    PDF »
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   Abstract »    Full Text »    PDF »
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X. Cheng and G. W. Hart (2001)
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   Abstract »    Full Text »    PDF »
The Multifaceted Mechanisms of Estradiol and Estrogen Receptor Signaling.
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Another role highlighted for estrogens in the male: Sexual behavior.
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   Full Text »    PDF »
Abolition of male sexual behaviors in mice lacking estrogen receptors alpha and beta (alpha beta ERKO).
S. Ogawa, A. E. Chester, S. C. Hewitt, V. R. Walker, J.-A. Gustafsson, O. Smithies, K. S. Korach, and D. W. Pfaff (2000)
PNAS 97, 14737-14741
   Abstract »    Full Text »    PDF »

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