Ligand-independent effects of estrogen receptor β on mouse gonadotropin-releasing hormone promoter activity

Toni R. Pak, Wilson C.J. Chung, James L. Roberts, Robert J. Handa

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

GnRH is the most upstream regulator of reproduction in vertebrates, and its synthesis and release are regulated by gonadal steroid hormones. The proposed sites of hormone action were historically thought to be upstream from GnRH neurons; however, the discovery of ERβ in a subset of GnRH neurons suggests that this hypothesis should be reevaluated. To determine a functional role for ERβ in GnRH neurons, we examined ERβ's regulation of GnRH promoter activity. The GnRH-producing cell line, GT1-7, was cotransfected with expression vectors containing one of three ERβ splice variants and a luciferase-reporter construct containing the full-length mouse GnRH promoter sequence or one of two deletions upstream of the transcription start site (-225/-201; -184/-150). Transfected cells were treated with 100 nM 17β-estradiol (E2), diarylpropionitrile, raloxifene, or vehicle. There was a robust increase in GnRH-luciferase activity by all ERβ splice variants in the absence of hormone. Furthermore, E2 treatment abolished this response for ER-β1 and ER-β2, but not ER-β1δ3. The -225/-201 and -184/-150 regions were critical for ERβ-induced promoter activity because deletion of these regions eliminated the ligand-independent effects of ERβ. ER-β1 binds directly to these promoter regions and because there are no classical estrogen response elements in the mouse GnRH promoter, these data raise the possibility that this region contains a novel estrogen response element specific for ERβ. Overall, our data suggest that ERβ functions as a basic transcription factor in GnRH neurons and demonstrate a potential molecular mechanism for the negative feedback effects of E2 on GnRH.

Original languageEnglish (US)
Pages (from-to)1924-1931
Number of pages8
JournalEndocrinology
Volume147
Issue number4
DOIs
StatePublished - Apr 2006

ASJC Scopus subject areas

  • Endocrinology

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