Estrogen response element-independent estrogen receptor (ER)-α signaling does not rescue sexual behavior but restores normal testosterone secretion in male ERα knockout mice

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Estrogen receptor (ER)-α mediates estradiol (E2) actions in the male gonads and brain and is critical for normal male reproductive function. In the classical pathway, ERα binds to estrogen response elements (EREs) to regulate gene transcription. ERα 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 ERα signaling can rescue the disrupted masculine sexual behaviors and elevated serum testosterone (T) levels that have been shown to result from ERα gene deletion. We utilized male ERα null mice that possess a ER knock-in mutation (E207A/G208A; AA), in which the mutant ERα is incapable of binding to DNA and can signal only through ERE-independent pathways (ERα-/AA mice). We found that sexual behavior, including mounting, is virtually absent in ERα-/- and ERα-/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 ERα -/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, whereas ERE-independent ERα signaling may mediate E2's inhibitory effects on T production.

Original languageEnglish (US)
Pages (from-to)5288-5294
Number of pages7
JournalEndocrinology
Volume148
Issue number11
DOIs
StatePublished - Nov 2007

ASJC Scopus subject areas

  • Endocrinology

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