Gonadotrophin-Releasing Hormone Drives Melatonin Receptor Down-Regulation in the Developing Pituitary Gland

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 5; pp. 2831 - 2835
• Main Authors: Johnston, Jonathan D., Messager, Sophie, Francis J. P. Ebling, Williams, Lynda M., Barrett, Perry, Hazlerigg, David G.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 04.03.2003; National Acad Sciences; The National Academy of Sciences
• Subjects: Animals; Biological Sciences; Cloning, Molecular; COS Cells; DNA, Complementary - metabolism; Down-Regulation; Endocrine cells; Endocrinology; Genes; Genes, Reporter; Gonadotropin-Releasing Hormone - physiology; Homeodomain Proteins - metabolism; Hormones; In Situ Hybridization; Luciferases - metabolism; Mammals; Melatonin - metabolism; Melatonin receptors; Messenger RNA; Mice; Molecular Sequence Data; Neurotransmitters; Paired Box Transcription Factors; Pituitary gland; Pituitary Gland - embryology; Pituitary Gland - metabolism; Plasmids - metabolism; Promoter Regions, Genetic; Protein Binding; Rats; Receptors, Cell Surface - biosynthesis; Receptors, Cytoplasmic and Nuclear - biosynthesis; Receptors, Melatonin; RNA, Messenger - metabolism; Transcription factors; Transcription Factors - metabolism; Transcriptional Activation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0436184100

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 MT1is 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 MT1gene expression in the rat pituitary gland. MT1mRNA 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 β-subunit (LHβ) 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 MT1gene 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 MT1-luciferase and LHβ-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 MT1-luciferase activity. Moreover, the transcription factor, early growth response factor-1, which is induced by gonadotrophin-releasing hormone (GnRH) and trans-activates LHβ expression, attenuated Pitx-1-induced MT1-luciferase activity. Finally, pituitary MT1gene 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 MT1gene expression.