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

Sep 17, 2014Proceedings of the National Academy of Sciences of the United States of America

Failure of embryo implantation in female mice after removing a key daily rhythm protein from hormone-producing ovarian cells

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Abstract

SF1-Bmal1(-/-) females exhibit embryonic implantation failure, which can be rescued by progesterone supplementation.

The circadian clock influences various aspects of female reproductive biology, including implantation.
Specific deletion of the Bmal1 gene in ovarian steroidogenic cells leads to implantation failure.
Transplantation of wild-type ovaries can restore implantation in SF1-Bmal1(-/-) females.
The central circadian clock remains functional despite the deletion in ovarian cells.
Ovarian transcriptome analysis shows disrupted expression of genes related to the circadian clock and progesterone regulation.

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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.

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

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