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: 3.32). 03/2008; 23(1):26-36. DOI: 10.1177/0748730407311254
Source: PubMed

ABSTRACT 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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Available from: Teri S Ord, Aug 14, 2015
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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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    Gene 07/2014; 548(1). DOI:10.1016/j.gene.2014.07.019 · 2.08 Impact Factor
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    • "The Clock mutant mice display a vast array of physiological defects, including metabolic syndrome, mania-like behavior, disrupted reproductive function, and reduced embryonic fibroblast proliferation (Turek et al. 2005; Miller et al. 2007; Roybal et al. 2007). Similarly, Bmal1-deficient mice have altered glucose metabolism, arrhythmic blood pressure, infertility , impaired adipocyte differentiation, and early aging (Shimba et al. 2005; Kondratov et al. 2006; Curtis et al. 2007; Alvarez et al. 2008; Lamia et al. 2008). These findings highlight the broad scope of physiology controlled by molecular clocks. "
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    • "Their results indicated an inability to carry on viable pregnancies and some degree of embryo lethality in these mice. The reason for this infertility remains unclear, but Alvarez et al. (2008) speculated that it was most likely to result from altered levels of reproductive hormones. We found that the TT genotype of ARNTL rs2278749 was linked to a higher number of pregnancies and a higher number of miscarriages, whereas and the Table 2. Genotype and allele frequencies and Hardy-Weinberg equilibrium estimate P-values. "
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