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Molecular and Cellular Biology, July 2000, p. 5261-5268, Vol. 20, No. 14
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Functional Compensation by Egr4 in Egr1-Dependent Luteinizing Hormone Regulation and Leydig Cell Steroidogenesis

Warren G. Tourtellotte,1,* Rakesh Nagarajan,2 Andrzej Bartke,3 and Jeffrey Milbrandt2,*

Department of Pathology and Neuroscience Institute, Northwestern University School of Medicine, Chicago, Illinois 606111; Department of Pathology and Laboratory Medicine,2 Washington University School of Medicine, St. Louis, Missouri 631102; and Department of Physiology, Southern Illinois University School of Medicine, Carbondale, Illinois 629013

Received 15 February 2000/Returned for modification 13 April 2000/Accepted 19 April 2000

The Egr family of zinc finger transcription factors, whose members are encoded by Egr1 (NGFI-A), Egr2 (Krox20), Egr3, and Egr4 (NGFI-C) regulate critical genetic programs involved in cellular growth, differentiation, and function. Egr1 regulates luteinizing hormone beta subunit (LHbeta ) gene expression in the pituitary gland. Due to decreased levels of LHbeta , female Egr1-deficient mice are anovulatory, have low levels of progesterone, and are infertile. By contrast, male mutant mice show no identifiable defects in spermatogenesis, testosterone synthesis, or fertility. Here, we have shown that serum LH levels in male Egr1-deficient mice are adequate for maintenance of Leydig cell steroidogenesis and fertility because of partial functional redundancy with the closely related transcription factor Egr4. Egr4-Egr1 double mutant male mice had low steady-state levels of serum LH, physiologically low serum levels of testosterone, and atrophy of androgen-dependent organs that were not present in either Egr1- or Egr4-deficient males. In double mutant male mice, atrophic androgen-dependent organs and Leydig cell steroidogenesis were fully restored by administration of exogenous testosterone or human chorionic gonadotropin (an LH receptor agonist), respectively. Moreover, a normal distribution of gonadotropin-releasing hormone-containing neurons and normal innervation of the median eminence in the hypothalamus, as well as decreased levels of LH gene expression in Egr4-Egr1-relative to Egr1-deficient male mice, indicates a defect of LH regulation in pituitary gonadotropes. These results elucidate a novel level of redundancy between Egr4 and Egr1 in regulating LH production in male mice.

* Corresponding author. Mailing address for Warren G. Tourtellotte: Northwestern University, Department of Pathology, W127, Ward Building, 7-112, 303 E. Chicago Ave., Chicago, IL 60611. Phone: (312) 503-2415. Fax: (312) 503-2459. E-mail: warren{at}northwestern.edu. Mailing address for Jeffrey Milbrandt: Washington University, Department of Pathology, Campus Box 8118, 660 S. Euclid Ave., St. Louis, MO 63110. Phone: (314) 362-4651. Fax: (314) 362-8756. E-mail: jeff{at}pathology.wustl.edu.

Molecular and Cellular Biology, July 2000, p. 5261-5268, Vol. 20, No. 14
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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