Abstract
Melatonin receptor expression exhibits profound developmental changes through poorly understood mechanisms. In mammals, a current model suggests that pubertal reactivation of gonadotrophin-releasing hormone (GnRH) secretion down-regulates MT1 melatonin receptors in pituitary gonadotroph cells, via the induction of early growth response factor-1 (EGR-1). Here we have examined this model by testing the hypotheses that inhibition of Mt1 expression by GnRH occurs directly in gonadotroph cells, can be reversed in adulthood by blockade of GnRH receptors, and requires EGR-1. We first confirmed the endogenous expression of Mt1 mRNA in the αT3-1 gonadotroph cell line. Stimulation of these cells with a GnRH agonist resulted in a rapid increase of Egr-1 mRNA expression, which peaked after 30–60 minutes, and a more prolonged elevation of nuclear EGR-1 immunoreactivity. Moreover, the GnRH agonist significantly decreased Mt1 mRNA. We then treated adult male rats with the GnRH antagonist cetrorelix or saline. After 4 weeks of daily injections, cetrorelix significantly reduced serum LH concentration and testis weight, with histological analysis confirming absence of spermatogenesis. Despite the successful inhibition of GnRH signalling, pituitary Mt1 expression was unchanged. Next we studied the proximal region of the rat Mt1 promoter. Consistent with previous work, over-expression of the transcription factor PITX-1 increased Mt1-luciferase reporter activity; this effect was dependent on the presence of consensus PITX-1 promoter binding regions. Over-expression of EGR-1 inhibited PITX-1-stimulated activity, even following mutation of the consensus EGR-1 binding site. Finally, we studied Egr1 −/− mice and observed no difference in pituitary Mt1 expression between Egr1 −/− and wild-type litter mates. This work demonstrates that GnRH receptor activation directly down-regulates Mt1 expression in gonadotroph cells. However, pituitary Mt1 expression in adults is unaltered by blockade of GnRH signalling or absence of EGR-1. Our data therefore suggest that melatonin receptor regulation by GnRH is not reversible in adulthood and doesn't require EGR-1.
Highlights
The hormone melatonin is implicated in multiple diverse aspects of physiology [1]
This study demonstrates that activation of gonadotrophin-releasing hormone (GnRH) receptors in gonadotroph cells down-regulates expression of Mt1 mRNA
Our previous studies led us to hypothesise that the perinatal decline in pituitary MT1 melatonin receptor expression is due to the pubertal reactivation of GnRH secretion from the hypothalamus
Summary
The hormone melatonin is implicated in multiple diverse aspects of physiology [1]. It is secreted into the blood and cerebrospinal fluid by the pineal gland, and is produced locally by other tissues within the body, such as the retina [2]. Pineal melatonin production is driven by the master circadian clock in the suprachiasmatic nuclei of the hypothalamus and exhibits a robust daily rhythm. In addition to control of rhythmic physiology, melatonin is reported to control many other biological processes One of these is suppression of the endocrine response of the developing pituitary gland to the key reproductive factor, gonadotrophin-releasing hormone (GnRH) [10]. Aspects of this work has methodological flaws [14,15] and other studies have failed to replicate the finding [17,18]
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