title: Molecular basis for the activation of gonadotropin-inhibitory hormone gene transcription by corticosterone.
abstract: The inhibitory effect of stress on reproductive function is potentially mediated by high concentrations of circulating glucocorticoids (GCs) acting via the GC receptor (GR). Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that inhibits gonadotropin secretion. GnIH may mediate stress-induced reproductive dysfunction. However, it is not yet known whether GC-bound GR is directly involved in GnIH transcription. Here, we demonstrated the localization of GR mRNA in GnIH neurons in the paraventricular nucleus of quail, suggesting that GC can directly regulate GnIH transcription. We next showed that 24 hours of treatment with corticosterone (CORT) increase GnIH mRNA expression in the quail diencephalon. We further investigated the mechanism of activation of GnIH transcription by CORT using a GnIH-expressing neuronal cell line, rHypoE-23, derived from rat hypothalamus. We found the expression of GR mRNA in rHypoE-23 cells and increased GnIH mRNA expression by 24 hours of CORT treatment. We finally characterized the promoter activity of rat GnIH gene stimulated by CORT. Through DNA deletion analysis, we identified a CORT-responsive region at 2000-1501 bp upstream of GnIH precursor coding region. This region included 2 GC response elements (GREs) at -1665 and -1530 bp. Mutation of -1530 GRE abolished CORT responsiveness. We also found CORT-stimulated GR recruitment at the GnIH promoter region containing the -1530 GRE. These results provide a putative molecular basis for transcriptional activation of GnIH under stress by demonstrating that CORT directly induces GnIH transcription by recruitment of GR to its promoter.
authors.affiliation: Laboratory of Integrative Brain Sciences (Y.L.S., T.U., M.N., Y.F., I.H., K.Y., K.T.), Department of Biology, Waseda University, and Center for Medical Life Science of Waseda University, Tokyo 162-8480, Japan; and Departments of Physiology (D.D.B.), Medicine, and Obstetrics and Gynaecology, University of Toronto, and Division of Cellular and Molecular Biology, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada M5S 1A8.
authors.forename: You Lee
authors.initials: YL
authors.lastname: Son
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Ubuka
authors.forename: Misato
authors.initials: M
authors.lastname: Narihiro
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Fukuda
authors.forename: Itaru
authors.initials: I
authors.lastname: Hasunuma
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Denise D
authors.initials: DD
authors.lastname: Belsham
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Tsutsui
mesh_terms: D024506:5' Flanking Region; D000818:Animals; D030161:Avian Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003345:Corticosterone / Q000378:metabolism*; D003370:Coturnix / Q000378:metabolism*; D017353:Gene Deletion; D007028:Hypothalamic Hormones / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D030161:Avian Proteins; D007028:Hypothalamic Hormones; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins; C413752:gonadotropin-inhibitory hormone, Coturnix japonica; D003345:Corticosterone