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This version published online on August 2, 2007
Endocrinology, doi:10.1210/en.2007-0673
A more recent version of this article appeared on November 1, 2007
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Submitted on May 21, 2007
Accepted on July 25, 2007

ERE-independent ER{alpha} signaling does not rescue sexual behavior but restores normal testosterone secretion in male ER{alpha}KO mice

Melissa A. McDevitt, Christine Glidewell-Kenney, Jeffrey Weiss, Pierre Chambon, J. Larry Jameson, and Jon E. Levine*

Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, USA; Department of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 USA; Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Collège de France, Illkirch Cedex, France

* To whom correspondence should be addressed. E-mail: jlevine{at}northwestern.edu.

Estrogen receptor alpha (ER{alpha}) mediates estradiol (E2) actions in the male gonads and brain and is critical for normal male reproductive function. In the classical pathway, ER{alpha} binds to estrogen response elements (EREs) to regulate gene transcription. ER{alpha} can also regulate gene transcription independently of EREs via protein-protein interactions with transcription factors, and additionally signal via rapid, nongenomic pathways originating at the cell membrane. This study assessed the degree to which ERE-independent ER{alpha} signaling can rescue the disrupted masculine sexual behaviors and elevated serum testosterone (T) levels that have been shown to result from ER{alpha} gene deletion. We utilized male ER{alpha} null mice that possess a ER knock-in mutation (E207A/G208A; "AA"), in which the mutant ER{alpha} is incapable of binding to DNA and can only signal through ERE-independent pathways (ER{alpha}-/AA mice). We found that sexual behavior, including mounting, is virtually absent in ER{alpha}-/- and ER{alpha}-/AA males, suggesting that ERE-independent signaling is insufficient to maintain any degree of normal sexual behavior in the absence of ERE binding. By contrast, ERE-independent signaling in the ER{alpha}-/AA mouse is sufficient to restore serum T levels to values observed in wild-type males. These data indicate that binding of ERs to EREs mediates most if not all of E2's effects on male sexual behavior, while ERE-independent ER{alpha} signaling may mediate E2's inhibitory effects on T production.
Key words: estrogen receptor alpha • sexual behavior • testosterone • ERE-independent signaling




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