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Endocrinology Vol. 140, No. 6 2733-2744
Copyright © 1999 by The Endocrine Society

ARTICLES

Targeted Disruption of the Estrogen Receptor-{alpha} Gene in Female Mice: Characterization of Ovarian Responses and Phenotype in the Adult1

David W. Schomberg, John F. Couse, Abir Mukherjee, Dennis B. Lubahn, M. Sar, Kelly E. Mayo and Kenneth S. Korach

Departments of Obstetrics and Gynecology and Cell Biology (D.W.S.), Duke University Medical Center, Durham, North Carolina 27710; the Receptor Biology Section (J.F.C., K.S.K.), Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709-2233; Departments of Biochemistry and Child Health (D.B.L.), University of Missouri, Columbia, Missouri 65211; the Departments of Biochemistry, Molecular and Cell Biology (A.M., K.E.M.), Northwestern University, Evanston, Illinois 60208-0835; and the Chemical Industry Institute of Toxicology (M.S.), Research Triangle Park, North Carolina 27709-2137

Address all correspondence and requests for reprints to: Dr. Kenneth Korach, NIH-NIEHS, P.O. Box 12233/111 Alexander Drive, Research Triangle Park, North Carolina 27709-2233. E-mail: korach{at}niehs.nih.gov

Targeted disruption of the mouse estrogen receptor-{alpha} gene (estrogen receptor-{alpha} knockout; ERKO) results in a highly novel ovarian phenotype in the adult. The ERKO mouse model was used to characterize ER{alpha}-dependent processes in the ovary. Visualization of the ovaries of 10-, 20-, and 50-day-old wild-type (WT) and ERKO mice showed that the ERKO phenotype developed between 20 and 50 days of age. Developmental progression through the primordial, primary, and antral follicle stages appeared normal, but functional maturation of preovulatory follicles was arrested resulting in atresia or in anovulatory follicles, which in many cases formed large, hemorrhagic cysts. Corpora lutea were absent, which also indicates that the normal biochemical and mechanical processes that accomplish ovulation were compromised.

Northern and ribonuclease protection analyses indicated that ERKO ovary FSH receptor (FSHR) messenger RNA (mRNA) expression was approximately 4-fold greater than in WT controls. Ovarian LH receptor (LHR) mRNA expression was also higher in the ERKO animals. Cellular localization studies by in situ hybridization analysis of ERKO ovaries showed a high level of LHR mRNA expression in the granulosa and thecal layers of virtually all the antral follicles. Ribonuclease protection analyses showed that ovarian progesterone receptor and androgen receptor mRNA expression were similar in the two groups. These results indicated that ER{alpha} action was not a prerequisite for LHR mRNA expression by thecal or granulosa cells or for ovarian expression of progesterone receptor mRNA.

Ovarian estrogen receptor ß (ERß) was detected immunohistochemically, was sharply compartmentalized to the granulosa cells, and was expressed approximately equally in the ERKO animals and the WT controls. In contrast, ER{alpha} staining was present in the thecal cells but not the granulosa cells of the WT animals.

The summary findings indicate that in the adult the major cause of the ERKO phenotype is high circulating LH interacting with functional LHR of the theca and granulosa cells. These features result in a failure of the normal maturational events leading to successful ovulation and luteinization and presumably involve both hypothalamic-pituitary and intraovarian mechanisms dependent upon ER{alpha} action. The presence of ERß in the granulosa cells did not rescue the phenotype of the ovary.




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