Article

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

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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    • "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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