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Impaired Steroidogenesis and Implantation Failure in Bmal1^–/– Mice

Departments of Pediatrics, Developmental Biology, and Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Louis J. Muglia, Departments of Pediatrics, Developmental Biology, and Obstetrics and Gynecology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8208, St. Louis, Missouri 63110. E-mail: louis.muglia{at}vanderbilt.edu.

Evidence in humans and rodents suggests that normal circadian rhythmicity is important for supporting reproductive function. A molecular clock underlies circadian rhythmicity. Impaired fertility is observed in some genetically altered mice with deficiencies in genes of the molecular clock, suggesting a critical role for these genes in reproduction. Here we systematically characterize the reproductive phenotype of females deficient in the clock gene Bmal1. Bmal1^–/– females are infertile. They exhibit progression through the estrous cycle, although these cycles are prolonged. Normal follicular development occurs in Bmal1^–/– females, and healthy embryos of the expected developmental stage are found in the reproductive tract of Bmal1^–/– females 3.5 d after mating to wild-type males. However, serum progesterone levels are significantly lower in Bmal1^–/– vs. Bmal1^+/± females on d 3.5 of gestation. Low progesterone levels in Bmal1^–/– females are accompanied by decreased expression of steroidogenic acute regulatory protein in corpora lutea of Bmal1^–/– vs. Bmal1^+/± females. Whereas implantation of embryos is not observed in untreated or vehicle-treated Bmal1^–/– females, exogenous administration of progesterone to Bmal1^–/– females is able to reinstitute implantation. These data suggest that implantation failure due to impaired steroidogenesis causes infertility of Bmal1^–/– females.

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