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
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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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    • "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.
    Poultry Science 02/2015; 94(5). DOI:10.3382/ps/pev057 · 1.67 Impact Factor
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    • "In order to identify clock gene functions in the testis, immunohistochemistry was used in former studies to locate certain clock genes or proteins in testicular sections. BMAL1 has been found to oscillate with a peak at CT3 in murine Leydig cells, where it is thought to be related to proper testosterone production since homozygous Bmal1 knockout males have low testosterone levels, accompanied by small testes, small seminal vesicles and decreased sperm counts (Alvarez et al., 2008). It has also been found together with CLOCK in the chromatoid body of murine round spermatids, that both proteins may participate in assembly and physiology of the chromatoid body in which RNA is processed (Peruquetti et al., 2012). "
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    ABSTRACT: Rhythmic oscillations that repeat every 24h can be found in numerous behavioral and physiological functions. Beside the endogenous master clock in the suprachiasmatic nucleus (SCN), peripheral oscillators exist that can disengage from the master clock rhythm by different mechanisms. The fact that core clock genes in peripheral tissues do not always have the same characteristics as in the SCN suggests that their function may vary in different organs. Additionally, suggestions about species-specific variation in expression peak and nadir times, especially in the testis, led to the need for systematical investigations on clock gene expression patterns in different organs and species under standardized methodological conditions. Therefore, daily gene expression patterns of the clock genes Bmal1, Period1, Period2, Clock, Cryptochrome1 and Cryptochrome2 were recorded at each of eight time points during a 24hour period in the testis, kidney, liver, spleen and heart of three hamster species (Phodopus sungorus, Phodopus roborovskii and Cricetulus griseus; family: Cricetidae). Clock gene expression was found to be rhythmic in all investigated organs, however with inconsistent results in the testis. Complex cosinor analysis revealed species differences in temporal gene expression patterns regarding their orthophase, number of peaks, and amplitude for all genes and organs with most pronounced differences in the testis. The results of this study strongly indicate that clock gene expression is species-specific and that their function in peripheral tissues might be at least partly connected to clock-unrelated traits that vary between the investigated species. Further studies should aim at clarifying the specific roles of clock genes in the testis.
    Gene 07/2014; 548(1). DOI:10.1016/j.gene.2014.07.019 · 2.14 Impact Factor
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    • "However, the findings of independent clocks in peripheral tissues (1, 9, 12–15) suggest a possible gonadal independent role in regulating the rhythmicity of gonadal steroids. In fact, recent findings support the assumption that some clock genes can influence fertility and testosterone (T) seasonality both in animals (16) and in humans (17). In particular, Brain and muscle Arnt-like protein 1 (BMAL1) and Neuronal PAS domain protein 2 (NPAS2) gene variants have been shown to influence fertility and seasonality in humans (17). "
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    ABSTRACT: Some environmental factors may influence the pituitary-gonadal function. Among these, light plays an important role in animals and in humans. The effect of light on the endocrine system is mediated by the pineal gland, through the modulation of melatonin secretion. In fact, melatonin secretion is stimulated by darkness and suppressed by light, thus its circadian rhythm peaks at night. Light plays a favorable action on the hypothalamic-pituitary axis likely inhibiting melatonin secretion, while the exogenous melatonin administration does not seem to impair the hormonal secretions of this axis. The basal and rhythmic pituitary-gonadal hormone secretions are regulated by a central clock gene and some independent clock genes in the peripheral tissues. Light is able to induce the expression of some of these genes, thus playing an important role in regulating the hormonal secretions of pituitary-gonadal axis and the sexual and reproductive function in animals and humans. The lack of light stimulus in blind subjects induces increase in plasma melatonin concentrations with a free-running rhythm of secretion, which impairs the hormonal secretions of pituitary-gonadal axis, causing disorders of reproductive processes in both sexes.
    Frontiers in Endocrinology 01/2014; 4:205. DOI:10.3389/fendo.2013.00205
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