Figure 3.

The molecular clock in mammalian follicular cells may drive the expression of clock-controlled genes necessary for ovulation. Circadian clock genes, including activators [BMAL1 (B); CLOCK (C)] and repressors [period (per) and cryptochrome (cry)], are rhythmically expressed and phosphorylated by casein kinases in granulosa cells. Cyclooxygenase-2 (cox2), the rate limiting enzyme for prostanoid synthesis, has E-box sequences in its promoter region, and evidence suggests that CLOCK:BMAL1 heterodimers can bind to and activate cox2 transcription [78, 79]. Circadian rhythms of cox2 mRNA expression may result in rhythmic accumulation of COX2 enzyme. In turn, rhythms of COX2 enzyme expression may lead to rhythmic synthesis and accumulation of PGE2 and PGF2α. Increased levels of prostanoid synthesis, particularly in response to a surge in LH secretion, are associated with follicular rupture. Thus, circadian rhythms of cox2 mRNA synthesis might indirectly contribute to the timing of ovulation by establishing a ready pool of LH-inducible prostaglandins. Transactivation by BMAL1:CLOCK is indicated by (+); repression of BMAL1:CLOCK activity by PER:CRY is indicated by (−). Arrowheads attached to sine waves indicate rhythmic transcription/translation. Curved arrows indicate nuclear translocation. Abbreviations: arachidonic acid (AA); prostaglandin E2 (PGE2); prostaglandin F2α (PGF2α); phosphorylation (P); Casein kinase 1,2 (CK1,2).