The investigation for an ovarian cellular clock in mice

Abstract

The formation of the ovarian follicles and the subsequent recruitment to proceed to ovulation is a complex mechanism involving both local and external signals. Early hormonal unresponsive follicles develop to a mature hormonal responsive antral follicle however, this transition is not completely understood. As ovulation in all mammals is heavily influenced by the light/dark cycle, which indicates the involvement of a cellular circadian clock in the development of ovarian follicles. The first reporting of a cellular clock mechanism was the circadian feedback loop found in the supachiasmic nucleus (SCN). This clock, which has further been identified in most mammalian tissues, hinges on the control over the BMAL1:CLOCK heterodimer. BMAL1:CLOCK bind E- box promotor region increasing transcription of genes which include Cry, Per and physiological function genes. CRY and PER are responsible for the negative regulation of the heterodimer, ultimately inhibit its ability unregulated transcript including its own. Using a mouse model, immunohistochemical studies has identified both protein expression and localization of seven proteins known to be involved in cellular clock regulation (CLOCK, BMAL1, CRY1, CRY2, PER1, PER2 and SIRT1). CLOCK and BMAL1 have shown to be in abundance in day (0900) sections. Conversely the four negative proteins and SIRT1, a regulator of the clock, have demonstrated greater levels of protein expression in night (0100) sections. This provides support the model of an ovarian cellular clock within the ovary. However, any variation in the cellular clock between the stages of follicle development was not in complete agreement with the hypothesis of a differential clock. The manipulation of ovulation (superovulation) did appear to disrupt the cellular clock, thus suggesting a link between these two cycles.