The Circadian Clock Protein BMAL1 Is Necessary for Fertility and Proper Testosterone Production in Mice

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Journal of Biological Rhythms (Impact Factor: 2.77). 03/2008; 23(1):26-36. DOI: 10.1177/0748730407311254
Source: PubMed


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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    • "In addition to regulating each other to sustain oscillations, REV-ERBa also controls the expression of numerous downstream genes through binding to ROREs at their promoters. BMAL1, a critical component of clock proteins, is indispensable in maintaining the integrity of the circadian feedback loop and the homeostasis of numerous behaviors and physiological processes (Kondratov et al. 2006;Alvarez et al. 2008;Grechez-Cassiau et al. 2008;Ratajczak et al. 2009). Several studies provided evidence demonstrating that the physiologic significance of BMAL1 is related to mammalian reproductive functions (Ratajczak et al. 2009;Boden et al. 2010;Liu et al. 2014). "
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    ABSTRACT: Cellular oscillators in the uterus play critical roles in the gestation processes of mammals through entraining of the clock proteins to numerous downstream genes, including growth/differentiation factor (Gdf)10 and Gdf15. The expression of Gdf10 and Gdf15 is significantly increased in the uterus during decidualization, but the mechanism underlying the regulation of Gdf gene expression in the uterus is poorly understood. Here, we focused on the function of the cellular oscillators in the expression of Gdf family by using uterine endometrial stromal cells (UESCs) isolated from pregnant Per2-dLuc transgenic rats. A significant decline of Per2-dLuc bioluminescence activity was induced in in vitro decidualized UESCs, and concomitantly the expression of canonical clock genes was downregulated. Conversely, the expression of Gdf10 and Gdf15 of the Gdf was upregulated. In UESCs transfected with Bmal1-specific siRNA, in which Rev-erbα expression was downregulated, Gdf10 and Gdf15 were upregulated. However, Gdf5, Gdf7, and Gdf11 were not significantly affected by Bmal1 silencing. The expression of Gdf10 and Gdf15 was enhanced after treatment with a REV-ERBα antagonist in the presence or absence of progesterone. Chromatin immunoprecipitation-PCR analysis revealed the inhibitory effect of REV-ERBα on the expression of Gdf10 and Gdf15 in UESCs by recognizing their gene promoters. Collectively, our findings indicate that the attenuation of REV-ERBα leads to an upregulation of Gdf10 and Gdf15 in decidual cells, in which cellular oscillators are impaired. Our results provide novel evidence regarding the functions of cellular oscillators regulating the expression of downstream genes during the differentiation of UESCs.
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    • "Global knockout (KO) of Bmal1 results in complete loss of circadian rhythmicity measured via wheel-running activity (Bunger et al., 2000). These mice are also sterile (Alvarez et al., 2008) and have shorter life spans than wild-type mice (Sun et al., 2006). They have a loss of circadian rhythmicity in HR and blood pressure and are also hypotensive compared to the wild-type mice (Curtis et al., 2007). "
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    ABSTRACT: Since the kidney is integral to maintenance of fluid and ion homeostasis, and therefore blood pressure regulation, its proper function is paramount. Circadian fluctuations in blood pressure, renal blood flow, glomerular filtration rate, and sodium and water excretion have been documented for decades, if not longer. Recent studies on the role of circadian clock proteins in the regulation of a variety of renal transport genes suggest that the molecular clock in the kidney controls circadian fluctuations in renal function. The circadian clock appears to be a critical regulator of renal function with important implications for the treatment of renal pathologies, which include chronic kidney disease and hypertension. The development, regulation, and mechanism of the kidney clock are reviewed here.
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    • "icular stimulating hormone ) secreted by the pi - tuitary gland have an important influence on reproduc - tion . Nakao et al . ( 2007 ) concluded that the circadian clock controlling the timing of ovulation is in the ovary and that Clock / BMAL1 acts additively with luteiniz - ing hormone , accelerating the development of a pre - ovulatory surge . Alvarez et al . ( 2008 ) found that both male and female BMAL1 knockout mice were infertile . Wunderer et al . ( 2013 ) also suggested that clock genes and their protein products may be directly involved in the photoperiod - dependent regulation and adaptation of hormone synthesis and release ."
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    ABSTRACT: We examined the effect of monochromatic light supplementation on pigeon reproductive performance and on the expression of the brain and muscle aryl hydrocarbon receptor nuclear translocator-like (BMAL1) protein in the hypothalamic-pituitary-gonadal (HPG) axis. White King pigeons were selected randomly from 4 lofts (510 pairs/loft) with 3 subgroups/loft. The lofts were exposed to one of 4 light treatments for 3 months administered in the morning and evening as follows: blue light (480 nm), green light (540 nm), red light (660 nm), and control white light. The laying rate, fertility rate, and birth rate were recorded. After 3 months, 48 birds were selected randomly from the 4 lofts (6 females and 6 males from each loft), sacrificed, and the HPG axis was isolated. Following exposure to red light, laying rate was greater than the control group (P = 0.013), but there were no significant differences in the fertility rate (P = 0.41) or birth rate (P = 0.66). Expression of BMAL1 in the hypothalamus was unaffected by the light regime but was greater in the pituitary of females exposed to red light (P = 0.046) and in the pituitary of males exposed to the control white light (P = 0.059). The change in BMAL1 expression in the pituitary of females was negatively correlated with birth rate in monochromatic light (P = 0.021). We suggest that reproductive performance of pigeons is improved by light supplementation in the morning and evening. According to these data, 100 pigeons exposed to red light could lay 26.68 more eggs per month than the control group. Additionally, BMAL1 expression in the HPG axis of pigeons exposed to monochromatic light correlated with birth rate. © 2015 Poultry Science Association Inc.
    Preview · Article · Feb 2015 · Poultry Science
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