Melatonin receptor 1-dependent gene expression in the mouse pars tuberalis as revealed by cDNA microarray analysis andin situhybridization

Abstract

Melatonin is an important rhythmic endocrine signal within the circadian system of mammals. The hypophyseal pars tuberalis (PT) is a major target for melatonin and shows a high density of melatonin type 1 receptors (MT1). Melatonin affects expression of clock genes in PT cells which encode for transcriptional regulators of rhythmic gene expression. In this study, microarray analysis was performed to screen for genes coding for transcriptional regulators under the control of MT1 receptors in the mouse PT. Gene expression levels were compared between melatonin-proficient mice deficient for MT1 (MT1-/-) and the corresponding wild-type (WT) during mid-subjective day (CT06, low endogenous melatonin levels) and mid-subjective night (CT18, high endogenous melatonin levels). In situ hybridization was used to validate the data obtained by microarray analysis to analyze the acute effect of daytime melatonin application on gene expression in the wild-type PT. In the wild-type PT, expression of Tim was higher during day as compared to night. These day/night differences in gene expression were not observed in the PT of MT1-/- mice, demonstrating the impact of MT1-mediated signal transduction pathway. Day-time application of melatonin acutely affected Tim and Cry1 expression but not Neurod1 and Npas4 expression. We conclude that melatonin regulates expression of genes coding for transcriptional regulators in the PT through MT1 receptors by either acute or long-term mechanisms.

Melatonin Receptor 1 Deficiency Affects Feeding Dynamics and Pro-Opiomelanocortin<b> </b>Expression in the Arcuate Nucleus and Pituitary of Mice

“…Another possibility may be that the melatonin signal affecting the POMC system and thus the Pomc expression in the ARC and PD is decoded in the hypophysial pars tuberalis which contains a high density of MT1 receptors [8] and conveys the MT1-mediated melatonin signal retrogradely via thyrotropin to the hypothalamus including the ARC and anterogradely via endocannabinoids to the PD [14,32,[49][50][51][52] .…”

“…F6/19) reported here were conducted in accordance with accepted standards of humane animal care and were consistent with Federal Guidelines and Directive of the European Union (2010/63/EU). Mice with a targeted deletion of the MT1 gene (MT1-/-) and the corresponding WT were bred onto melatonin-proficient C3H/HeN background for at least 10 generations [14,32,33] . Experiments were performed with adult (10-to 18-week-old) male littermates obtained by heterozygous breeding.…”

“…In general, melatonin can act upon two high-affinity melatonin receptors, MT1 and MT2 (formerly Mel1a and Mel1b) [5][6][7][8] . However, several studies suggest that it is mainly the MT1 receptor which mediates melatonin signaling to the hypothalamohypophysial axis [9][10][11][12][13][14] .…”

Mistimed sleep disrupts circadian regulation of the human transcriptome

“…What are the mechanisms underlying persistent rhythmicity and loss of rhythmicity? The circadian rhythms of both melatonin and cortisol are known to regulate gene expression (11,43) and are driven by the SCN. The fact that the vast majority of circadian transcripts become arrhythmic when sleeping out of phase with melatonin would indicate that the SCN neural outputs and hormones driven by the SCN (i.e., melatonin and cortisol only has a limited influence on the peripheral blood).…”

Encoding and Decoding Photoperiod in the Mammalian Pars Tuberalis

“…Per1 ) by a cAMP-mediated mechanism, melatonin is also known to directly activate gene transcription at the onset of darkness. Melatonin-dependent transcriptional activation in the PT was shown in both sheep and melatonin-proficient C3H mice [98,99,100] with the best studied example being Cry1 . This upregulation occurs very quickly at dusk and the pathways involved, presumably involving cAMP independent mechanisms, remain uncharacterised.…”