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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

Amanda Hansen

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA

Teri Ord

Center for Research on Reproduction and Women's Health, University of Pennsylvania School of Medicine, Philadelphia, PA

Piotr Bebas

Department of Animal Physiology, University of Warsaw, Poland, Department of Zoology, Oregon State University, Corvallis, OR

Patrick E. Chappell

Department of Zoology, Oregon State University, Corvallis, OR

Jadwiga M. Giebultowicz

Department of Zoology, Oregon State University, Corvallis, OR

Carmen Williams

Center for Research on Reproduction and Women's Health, University of Pennsylvania School of Medicine, Philadelphia, PA

Stuart Moss

Center for Research on Reproduction and Women's Health, University of Pennsylvania School of Medicine, Philadelphia, PA

Amita Sehgal

Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, PA, amita{at}mail.med.upenn.edu, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, PA

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.

Key Words: circadian rhythms • fertility • testosterone • testes • sperm • StAR • mice

Journal of Biological Rhythms, Vol. 23, No. 1, 26-36 (2008)
DOI: 10.1177/0748730407311254


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