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Egr1 involvement in evening gene regulation by melatonin

J. M. Fustin^*, H. Dardente^*, G. C. Wagner^*, D. A. Carter, J. D. Johnston, G. A. Lincoln and D. G. Hazlerigg^*,1

^* Department of Zoology, School of Biological Sciences, Aberdeen University, Aberdeen, UK;

Cardiff School of Biosciences, Cardiff, UK;

University of Surrey, Guildford, UK; and

Centre for Reproductive Biology, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

¹Correspondence: Aberdeen University, School of Biological Sciences, Zoology, Tillydrone Avenue, Aberdeen, AB242TZ, Scotland, UK. E-mail: d.hazlerigg{at}abdn.ac.uk

Seasonal photoperiodic responses in mammals depend on the pineal hormone melatonin. The pars tuberalis (PT) region of the anterior pituitary has emerged as a principal melatonin target tissue, controlling endocrine responses. Rising melatonin levels acutely influence the expression of a small cluster of genes either positively (exemplified by cryptochrome-1, cry1) or negatively (exemplified by the type 1 melatonin receptor, mt1). The purpose of this study was to characterize the pathways through which these evening actions of melatonin are mediated. In vitro experiments showed that cAMP signaling in the PT directly influences mt1 but not cry1 expression. Analysis of nuclear extracts from sheep PT tissue collected 90 min after melatonin or saline control injections highlighted the response element for the immediate early gene egr1 (EGR1-RE) as a candidate for acute melatonin-dependent transcriptional regulation. We identified putative EGR1-RE’s in the proximal promoter regions of the ovine cry1 and mt1 genes, and confirmed their functionality in luciferase reporter assays. Egr1 expression is suppressed by melatonin in PT cell cultures, and is rhythmic in the ovine PT with a nadir in the early night. We propose that melatonin-dependent effects on EGR1-RE’s contribute to evening gene expression profiles in this pituitary melatonin target tissue.—Fustin J. M., Dardente H., Wagner G. C., Carter D. A., Johnston J. D., Lincoln G. A., Hazlerigg D. G. Egr1 involvement in evening gene regulation by melatonin.

Key Words: pars tuberalis • clock gene • cryptochrome • photoperiod • circadian