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      Clocks Underneath: The Role of Peripheral Clocks in the Timing of Female Reproductive Physiology


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          The central circadian pacemaker in the suprachiasmatic nucleus (SCN) is a critical component of the neuroendocrine circuit controlling gonadotropin secretion from the pituitary gland. The SCN conveys photic information to hypothalamic targets including the gonadotropin releasing hormone neurons. Many of these target cells are also cell autonomous clocks. It has been suggested that, rather then being singularly driven by the SCN, the timing of gonadotropin secretion depends on the activity of multiple hypothalamic oscillators. While this view provides a novel twist to an old story, it does little to diminish the central role of rhythmic hypothalamic output in this system. It is now clear that the pituitary, ovary, uterus, and oviduct have functional molecular clocks. Evidence supports the notion that the clocks in these tissues contribute to the timing of events in reproductive physiology. The aim of this review is to highlight the current evidence for molecular clock function in the peripheral components of the female hypothalamo-pituitary-gonadal axis as it relates to the timing of gonadotropin secretion, ovulation, and parturition.

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          The circadian clock protein BMAL1 is necessary for fertility and proper testosterone production in mice.

          Although it is well established that the circadian clock regulates mammalian reproductive physiology, the molecular mechanisms by which this regulation occurs are not clear. The authors investigated the reproductive capacity of mice lacking Bmal1 (Arntl, Mop3), one of the central circadian clock genes. They found that both male and female Bmal1 knockout (KO) mice are infertile. Gross and microscopic inspection of the reproductive anatomy of both sexes suggested deficiencies in steroidogenesis. Male Bmal1 KO mice had low testosterone and high luteinizing hormone serum concentrations, suggesting a defect in testicular Leydig cells. Importantly, Leydig cells rhythmically express BMAL1 protein, suggesting peripheral control of testosterone production by this clock protein. Expression of steroidogenic genes was reduced in testes and other steroidogenic tissues of Bmal1 KO mice. In particular, expression of the steroidogenic acute regulatory protein (StAR) gene and protein, which regulates the rate-limiting step of steroidogenesis, was decreased in testes from Bmal1 KO mice. A direct effect of BMAL1 on StAR expression in Leydig cells was indicated by in vitro experiments showing enhancement of StAR transcription by BMAL1. Other hormonal defects in male Bmal1 KO mice suggest that BMAL1 also has functions in reproductive physiology outside of the testis. These results enhance understanding of how the circadian clock regulates reproduction.
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            Ovulation: new dimensions and new regulators of the inflammatory-like response.

            Ovulation is a complex process that is initiated by the lutenizing hormone surge and is controlled by the temporal and spatial expression of specific genes. This review focuses on recent endocrine, biochemical, and genetic information that has been derived largely from the identification of new genes that are expressed in the ovary, and from knowledge gained by the targeted deletion of genes that appear to impact the ovulation process. Two main areas are described in most detail. First, because mutant mouse models indicate that appropriate formation of the cumulus matrix is essential for successful ovulation, genes expressed in the cumulus cells and those that control cumulus expansion are discussed. Second, because mice null for the progesterone receptor fail to ovulate and are ideal models for dissecting the critical events downstream of progesterone receptor, genes expressed in mural granulosa cells that regulate the expression of novel proteases are described.
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              A 24-hour periodicity in the "LH-release apparatus" of female rats, disclosed by barbiturate sedation.


                Author and article information

                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                11 June 2013
                23 July 2013
                : 4
                : 91
                [1] 1Department of Medicine, Division of Endocrinology and Metabolism, School of Medicine and Dentistry, University of Rochester , Rochester, NY, USA
                Author notes

                Edited by: James Olcese, Florida State University College of Medicine, USA

                Reviewed by: Ted H. Elsasser, United States Department of Agriculture, USA; Heike Muenzberg-Gruening, Pennington Biomedical Research Center, USA; Tamara Castañeda, German Diabetes Center, Germany

                *Correspondence: Michael T. Sellix, Department of Medicine, Division of Endocrinology and Metabolism, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA e-mail: michael_sellix@ 123456urmc.rochester.edu

                This article was submitted to Frontiers in Systems and Translational Endocrinology, a specialty of Frontiers in Endocrinology.

                Copyright © 2013 Sellix.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                : 23 April 2013
                : 08 July 2013
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 83, Pages: 6, Words: 5606
                Mini Review

                Endocrinology & Diabetes
                clock gene,reproduction,fertility,circadian rhythm,ovary,uterus,oviduct,pituitary gland


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