title: Gonadotrophin-releasing hormone drives melatonin receptor down-regulation in the developing pituitary gland.
abstract: Melatonin is produced nocturnally by the pineal gland and is a neurochemical representation of time. It regulates neuroendocrine target tissues through G-protein-coupled receptors, of which MT(1) is the predominant subtype. These receptors are transiently expressed in several fetal and neonatal tissues, suggesting distinct roles for melatonin in development and that specific developmental cues define time windows for melatonin sensitivity. We have investigated MT(1) gene expression in the rat pituitary gland. MT(1) mRNA is confined to the pars tuberalis region of the adult pituitary, but in neonates extends into the ventral pars distalis and colocalizes with luteinizing hormone beta-subunit (LH beta) expression. This accounts for the well documented transient sensitivity of rat gonadotrophs to melatonin in the neonatal period. Analysis of an upstream fragment of the rat MT(1) gene revealed multiple putative response elements for the transcription factor pituitary homeobox-1 (Pitx-1), which is expressed in the anterior pituitary from Rathke's pouch formation. A Pitx-1 expression vector potently stimulated expression of both MT(1)-luciferase and LH beta-luciferase reporter constructs in COS-7 cells. Interestingly, transcription factors that synergize with Pitx-1 to trans-activate gonadotroph-associated genes did not potentiate Pitx-1-induced MT(1)-luciferase activity. Moreover, the transcription factor, early growth response factor-1, which is induced by gonadotrophin-releasing hormone (GnRH) and trans-activates LH beta expression, attenuated Pitx-1-induced MT(1)-luciferase activity. Finally, pituitary MT(1) gene expression was 4-fold higher in hypogonadal (hpg) mice, which do not synthesize GnRH, than in their wild-type littermates. These data suggest that establishment of a mature hypothalamic GnRH input drives the postnatal decline in pituitary MT(1) gene expression.
authors.affiliation: School of Biological Sciences, University of Aberdeen, Aberdeen AB24 5UA, United Kingdom.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Johnston
authors.forename: Sophie
authors.initials: S
authors.lastname: Messager
authors.forename: Francis J P
authors.initials: FJ
authors.lastname: Ebling
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Williams
authors.forename: Perry
authors.initials: P
authors.lastname: Barrett
authors.forename: David G
authors.initials: DG
authors.lastname: Hazlerigg
mesh_terms: D000818:Animals; D019556:COS Cells; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D017930:Genes, Reporter; D007987:Gonadotropin-Releasing Hormone / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism; D017403:In Situ Hybridization; D008156:Luciferases / Q000378:metabolism; D008550:Melatonin / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D051761:Paired Box Transcription Factors; D010902:Pituitary Gland / Q000196:embryology* / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D044094:Receptors, Melatonin; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D018076:DNA, Complementary; D018398:Homeodomain Proteins; D051761:Paired Box Transcription Factors; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D014157:Transcription Factors; C101485:homeobox protein PITX1; D007987:Gonadotropin-Releasing Hormone; D008156:Luciferases; D008550:Melatonin