Impaired steroidogenesis and implantation failure in Bmal1-/- mice.
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.
Ratajczak
Christine K
CK
Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Boehle
Katie L
KL
Muglia
Louis J
LJ
D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000502:physiology; D003338:Corpus Luteum / Q000378:metabolism; D010064:Embryo Implantation / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D030762:Estrous Cycle / Q000235:genetics; D005260:Female; D017403:In Situ Hybridization; D007247:Infertility, Female / Q000235:genetics*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010750:Phosphoproteins / Q000235:genetics; D011247:Pregnancy; D011374:Progesterone / Q000097:blood / Q000494:pharmacology; D000098682:Steroidogenic Acute Regulatory Protein
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D010750:Phosphoproteins; D011374:Progesterone; D000098682:Steroidogenic Acute Regulatory Protein; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse