UC San Diego

The luteinizing hormone (LH) surge, which prompts ovulation, is dependent on the coincidence of multiple molecular cues. Specifically, estrogen signaling and circadian rhythms work together to gate the LH surge. Although previous studies have shown that the absence of either the estrogen receptor α (ERα) or the circadian clock results in anovulation, the mechanisms behind these regulatory components are not well understood. Kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) initiate the cascade of hormones that ultimately cause the LH surge, and it is thought that these neurons are the location of integration of ERα and circadian rhythm signaling. In this study, we sought to elucidate mechanisms by which ERα signaling and circadian rhythms regulate the expression of the Kiss1 promoter. We found that estrogen induces the Kiss1 promoter after both 12 and 24 hours of treatment, and that this induction is dependent on the expression of ERα. On a finer temporal scale, estrogen-induced Kiss1 promoter expression may be dynamic in vitro, but the expression pattern is not circadian, indicating that estrogen signaling through ERα alone is not sufficient to drive circadian expression of Kiss1. We also found that the molecular clock protein Period 2 (Per2) is capable of inducing the Kiss1 promoter. Taken together, these data indicate that ERα and Per2 regulate the Kiss1 promoter and may be involved in the temporally controlled, estrogen-dependent LH surge.