Endocrine Abstracts (2002) 3 P173

Developmental regulation of the mt1 melatonin receptor gene in the rat pituitary gland

JD Johnston1, S Messager2, P Barrett3 & DG Hazlerigg1

1Department of Agriculture and Forestry, University of Aberdeen, Aberdeen, UK; 2Paradigm Therapeutics Ltd, Cambridge, UK; 3Rowett Research Institute, Aberdeen, UK.

Expression of the mt1 melatonin receptor has been described in both the pars tuberalis (PT) and pars distalis (PD) of the rat pituitary gland. Expression of mt1 mRNA and iodomelatonin (IMEL) binding sites is high in the neonate PD but rapidly declines over the initial weeks of postnatal life. In contrast, both mt1 mRNA and IMEL binding sites are preserved in the PT through to adulthood, leading to a marked tissue-specific expression profile.

To identify mechanisms that control mt1 regulation, we have cloned and characterised 1.5kb of the 5'-flanking region of the rat mt1 gene. Primary sequence analysis of this promoter revealed multiple putative cis-elements for Ptx1, a homeobox transcription factor. Expression of Ptx1 occurs throughout the developing embryonic pituitary but is restricted, primarily to the PT, in the adult gland. Furthermore, in vitro transfection of COS-7 cells with Ptx1 induced a large, dose-dependent stimulation of a mt1-luciferase reporter construct. Removal of the putative Ptx1 cis-elements by truncation of the mt1 promoter greatly attenuated this effect.

Subsequent studies investigated the interaction between Ptx1 and other transcription factors involved in pituitary development and function, including SF-1 and Egr1. In contrast to the well-defined synergism between Ptx1, SF-1 and Egr1 on the luteinising hormone beta-subunit promoter, the stimulation of the mt1 promoter by Ptx1 was strongly inhibited by Egr1 and not altered by SF-1.

These data support the hypotheses that 1) the developmental expression profile of mt1 in the rat pituitary gland is primarily driven by the homeobox transcription factor Ptx1, and 2) the stimulation of mt1 promoter activity by Ptx1 is modulated by complex interactions with other transcription factors, in a manner distinct from that previously observed for other genes expressed within the pituitary.

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