Journal Article

Loss of BMAL1 in ovarian steroidogenic cells results in implantation failure in female mice

Liu, Yan, Wallisser, Jacqueline A., Krentz, Kathy J., Moran, Susan M., Bradfield, Christopher A., Sullivan, Ruth, Schuler, Linda A., Glover, Edward, Parlow, Albert F., Drinkwater, Norman R., Johnson, Brian P., Shen, Anna L.

2014

Overview

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. Significance This work demonstrates that specific peripheral clocks play unique and discrete roles in specific aspects of reproductive biology. Our use of a cell-specific conditional knockout model, in coordination with ovary transplant technology, permits examination of a peripheral clock without the impacts of off-target deletions that might indirectly impact reproductive function. In this case, we show that the molecular circadian clock, found in ovarian steroidogenic cells, is crucial for normal female reproduction, specifically embryonic implantation. The observation that implantation can be rescued by a single ovary with normal molecular clock machinery [i.e., brain muscle arnt-like 1 (BMAL1)] may provide direction for clinical intervention strategies when aberrant circadian oscillations are influencing fertility.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Aging - genetics / Aging - physiology / animal ovaries / Animal reproduction / Animals / ARNTL Transcription Factors - deficiency / ARNTL Transcription Factors - genetics / ARNTL Transcription Factors - physiology / Biological Sciences / brain / Cells / Circadian rhythm / Circadian Rhythm - genetics / Circadian Rhythm - physiology / Circadian rhythms / Embryo implantation / Embryo Implantation - drug effects / Embryo Implantation - genetics / Embryo Implantation - physiology / Estrus - genetics / Estrus - physiology / Female / Female animals / Females / Gene expression / Gene Expression Profiling / Genes / Male / Mating behavior / Mice / Mice, Inbred C57BL / Mice, Knockout / muscles / Ovaries / Ovary - cytology / Ovary - physiology / Ovary - transplantation / Ovulation / Pregnancy / Progesterone - administration & dosage / Promoter Regions, Genetic / Reproduction / Reproductive system / Rodents / Sexual Maturation - genetics / Sexual Maturation - physiology / Steroidogenic Factor 1 - genetics / Steroids - biosynthesis / Transplantation