title: Sex differences in estrogen-dependent transcription of gonadotropin-releasing hormone (GnRH) gene revealed in GnRH transgenic mice.
abstract: The mechanisms through which gonadal steroids exert feedback actions on the activity of the GnRH neurons are not understood. Using a series of GnRH-LacZ transgenic mice we have examined the manner in which gonadal steroids suppress GnRH mRNA expression in male and female mice. The long-term gonadectomy of 5.5-GNZ-3.5 transgenic mice resulted in significant increases in cellular GnRH mRNA expression (P < 0.05) and plasma LH concentrations (P < 0.01) in both sexes. However, cellular levels of LacZ mRNA and beta-galactosidase, which provide an index of GnRH gene transcription, were only elevated in males after gonadectomy. This sexually differentiated response was also observed in mice gonadectomized for 2 wk. Estrogen replacement in gonadectomized males returned transgene expression to intact levels. Experiments in transgenic mice with 3' and 5' deleted GnRH-LacZ constructs revealed that the suppressive influence of estrogen on LacZ transcription in the male required a critical element located between -5.2 and -1.7 kb of the GnRH promoter. These studies show that the suppression of GnRH mRNA expression by estrogen in the male involves a decrease in GnRH gene transcription that is dependent on a distal GnRH promoter element. The same mechanism does not exist in females, indicating that gonadal steroids suppress GnRH mRNA levels in a sexually dimorphic manner.
authors.affiliation: Laboratory of Neuroendocrinology, The Babraham Institute, Cambridge CB2 4AT, United Kingdom.
authors.forename: Niren R
authors.initials: NR
authors.lastname: Thanky
authors.forename: Ruth
authors.initials: R
authors.lastname: Slater
authors.forename: Allan E
authors.initials: AE
authors.lastname: Herbison
mesh_terms: D000818:Animals; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000032:analysis / Q000235:genetics*; D007150:Immunohistochemistry; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009474:Neurons / Q000737:chemistry; D009919:Orchiectomy; D010052:Ovariectomy; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012727:Sex Characteristics; D014158:Transcription, Genetic / Q000187:drug effects*; D001616:beta-Galactosidase / Q000032:analysis / Q000235:genetics
chemical_list: D004967:Estrogens; D012333:RNA, Messenger; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D001616:beta-Galactosidase