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Ligand-Independent Effects of Estrogen Receptor ß on Mouse Gonadotropin-Releasing Hormone Promoter Activity

Department of Biomedical Science, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523

Address all correspondence and requests for reprints to: Toni R. Pak, Department of Biomedical Sciences, College of Veterinary Medicine, Colorado State University, Fort Collins, Colorado 80523. E-mail: Toni.Pak{at}colostate.edu.

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 ERß in a subset of GnRH neurons suggests that this hypothesis should be reevaluated. To determine a functional role for ERß in GnRH neurons, we examined ERß’s regulation of GnRH promoter activity. The GnRH-producing cell line, GT1–7, was cotransfected with expression vectors containing one of three ERß 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 17ß-estradiol (E₂), diarylpropionitrile, raloxifene, or vehicle. There was a robust increase in GnRH-luciferase activity by all ERß splice variants in the absence of hormone. Furthermore, E₂ treatment abolished this response for ER-ß1 and ER-ß2, but not ER-ß13. The –225/–201 and –184/–150 regions were critical for ERß-induced promoter activity because deletion of these regions eliminated the ligand-independent effects of ERß. ER-ß1 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 ERß. Overall, our data suggest that ERß functions as a basic transcription factor in GnRH neurons and demonstrate a potential molecular mechanism for the negative feedback effects of E₂ on GnRH.

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