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−/− 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.ovary | circadian rhythm | fertility | steroidogenesis

Developmental Programming by Androgen Affects the Circadian Timing System in Female Mice1

“…Thus, any disorder that alters or abolishes normal patterns of hormone secretion might be expected to have significant detrimental effects on circadian organization. The inverse relationship has already been established; that is, mutations affecting the circadian clock have been shown to alter steroid hormone synthesis and secretion [15,59]. Our results provide further evidence that internal circadian misalignment may be a critical factor in the etiology of complex disorders affecting both reproduction and metabolism.…”

“…It has been reported that the ovarian clock regulates the timing of sensitivity to endocrine signals, including the rhythmic secretion of gonadotropins [14]. Others have linked circadian clock function to reproductive physiology, with particular emphasis on steroid hormone synthesis [15,16]. Mutations that suppress clock function have dramatic impacts on fertility, including irregular LH secretion, abnormal cycles and implantation failure [17,18].…”

Inhibitory role of REV-ERBα in the expression of bone morphogenetic protein gene family in rat uterus endometrium stromal cells

“…Recent genetic studies strongly suggest an important role of Bmal1 in mammalian reproductive physiology (8,38,46). Bmal1 Ϫ/Ϫ mice are infertile with implantation failure and impaired steroidogenesis.…”

Circadian Clock Function in the Mammalian Ovary

“…Further, bmal1-/-mice have abnormally low levels of progesterone secretion due to reduced StAR expression (Ratajczak et al, 2009). It was recently reported that mice with a conditional knockout of the BMAL1 locus in steroidogenic cells (steroidogenicfactor 1-Cre; Bmal1flx/flx) show severe deficits in implantation success and compromised progesterone secretion (Liu et al, 2014). It was recently reported that mice with a conditional knockout of the BMAL1 locus in steroidogenic cells (steroidogenicfactor 1-Cre; Bmal1flx/flx) show severe deficits in implantation success and compromised progesterone secretion (Liu et al, 2014).…”