title: Loss of BMAL1 in ovarian steroidogenic cells results in implantation failure in female mice.
abstract: The circadian clock plays a significant role in many aspects of female reproductive biology, including estrous cycling, ovulation, embryonic implantation, onset of puberty, and parturition. In an effort to link cell-specific circadian clocks to their specific roles in female reproduction, we used the promoter that controls expression of Steroidogenic Factor-1 (SF1) to drive Cre-recombinase-mediated deletion of the brain muscle arnt-like 1 (Bmal1) gene, known to encode an essential component of the circadian clock (SF1-Bmal1(-/-)). The resultant SF1-Bmal1(-/-) females display embryonic implantation failure, which is rescued by progesterone supplementation, or bilateral or unilateral transplantation of wild-type ovaries into SF1-Bmal1(-/-) dams. The observation that the central clock, and many other peripheral clocks, are fully functional in this model allows the assignment of the implantation phenotype to the clock in ovarian steroidogenic cells and distinguishes it from more general circadian related systemic pathology (e.g., early onset arthropathy, premature aging, ovulation, late onset of puberty, and abnormal estrous cycle). Our ovarian transcriptome analysis reveals that deletion of ovarian Bmal1 disrupts expression of transcripts associated with the circadian machinery and also genes critical for regulation of progesterone production, such as steroidogenic acute regulatory factor (Star). Overall, these data provide a powerful model to probe the interlocking and synergistic network of the circadian clock and reproductive systems.
authors.affiliation: McArdle Laboratory for Cancer Research, and Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI 53706;
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: McArdle Laboratory for Cancer Research, and Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI 53706;
authors.forename: Brian P
authors.initials: BP
authors.lastname: Johnson
authors.affiliation: McArdle Laboratory for Cancer Research, and Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI 53706;
authors.forename: Anna L
authors.initials: AL
authors.lastname: Shen
authors.affiliation: McArdle Laboratory for Cancer Research, and Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI 53706;
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Wallisser
authors.affiliation: McArdle Laboratory for Cancer Research, and Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI 53706;
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Krentz
authors.affiliation: McArdle Laboratory for Cancer Research, and Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI 53706;
authors.forename: Susan M
authors.initials: SM
authors.lastname: Moran
authors.affiliation: McArdle Laboratory for Cancer Research, and Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI 53706; Research Animal Resources Center, University of Wisconsin-Madison, Madison, WI 53706; and.
authors.forename: Ruth
authors.initials: R
authors.lastname: Sullivan
authors.affiliation: McArdle Laboratory for Cancer Research, and Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI 53706;
authors.forename: Edward
authors.initials: E
authors.lastname: Glover
authors.affiliation: National Hormone and Peptide Program, Harbor-University of California Los Angeles Medical Center, Torrance, CA 90502.
authors.forename: Albert F
authors.initials: AF
authors.lastname: Parlow
authors.affiliation: McArdle Laboratory for Cancer Research, and Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI 53706;
authors.forename: Norman R
authors.initials: NR
authors.lastname: Drinkwater
authors.affiliation: Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI 53706; Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison WI 53706;
authors.forename: Linda A
authors.initials: LA
authors.lastname: Schuler
authors.affiliation: McArdle Laboratory for Cancer Research, and Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison WI 53706; bradfield@oncology.wisc.edu.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Bradfield
mesh_terms: D056930:ARNTL Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D000375:Aging / Q000235:genetics / Q000502:physiology; D000818:Animals; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology; D010064:Embryo Implantation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004971:Estrus / Q000235:genetics / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010053:Ovary / Q000166:cytology* / Q000502:physiology* / Q000637:transplantation; D011247:Pregnancy; D011374:Progesterone / Q000008:administration & dosage; D011401:Promoter Regions, Genetic; D012741:Sexual Maturation / Q000235:genetics / Q000502:physiology; D054339:Steroidogenic Factor 1 / Q000235:genetics; D013256:Steroids / Q000096:biosynthesis*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D054339:Steroidogenic Factor 1; D013256:Steroids; C515058:steroidogenic factor 1, mouse; D011374:Progesterone
keywords: circadian rhythm; fertility; ovary; steroidogenesis