title: The circadian clock protein BMAL1 is necessary for fertility and proper testosterone production in mice.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Alvarez
authors.forename: Amanda
authors.initials: A
authors.lastname: Hansen
authors.forename: Teri
authors.initials: T
authors.lastname: Ord
authors.forename: Piotr
authors.initials: P
authors.lastname: Bebas
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Chappell
authors.forename: Jadwiga M
authors.initials: JM
authors.lastname: Giebultowicz
authors.forename: Carmen
authors.initials: C
authors.lastname: Williams
authors.forename: Stuart
authors.initials: S
authors.lastname: Moss
authors.forename: Amita
authors.initials: A
authors.lastname: Sehgal
mesh_terms: D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000235:genetics* / Q000502:physiology*; D005298:Fertility / Q000502:physiology*; D005307:Fertilization in Vitro; D005640:Follicle Stimulating Hormone / Q000097:blood; D006728:Hormones / Q000097:blood; D007150:Immunohistochemistry; D007246:Infertility / Q000235:genetics; D008156:Luciferases / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013075:Sperm Capacitation / Q000502:physiology; D013076:Sperm Count; D013739:Testosterone / Q000096:biosynthesis*; D014162:Transfection
chemical_list: D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D005640:Follicle Stimulating Hormone; D006728:Hormones; D008156:Luciferases; D007986:Luteinizing Hormone; D012313:RNA; D013739:Testosterone; C538961:Bmal1 protein, mouse