Gonadotropic regulation of circadian clockwork in rat granulosa cells

Abstract

The circadian clock is responsible for the generation of circadian rhythms in hormonal secretion and metabolism. These peripheral clocks could be reset by various cues in order to adapt to environmental variations. The ovary can be characterized as having highly dynamic physiology regulated by gonadotropins. Here, we aimed to address the status of circadian clock in the ovary, and to explore how gonadotropins could regulate clockwork in granulosa cells (GCs). To this end, we mainly utilized the immunohistochemistry, RT-PCR, and real-time monitoring of gene expression methods. PER1 protein was constantly abundant across the daily cycle in the GCs of immature ovaries. In contrast, PER1 protein level was obviously cyclic through the circadian cycle in the luteal cells of pubertal ovaries. In addition, both FSH and LH induced Per1 expression in cultured immature and mature GCs, respectively. The promoter analysis revealed that the Per1 expression was mediated by the cAMP response element binding protein. In cultured transgenic GCs, both FSH and LH also induced the circadian oscillation of Per2. However, the Per2 oscillation promoted by FSH quickly dampened within only one cycle, whereas the Per2 oscillation promoted by LH was persistently maintained. Collectively, these findings strongly suggest that both FSH and LH play an important role in regulating circadian clock in the ovary; however, they might exert differential actions on the clockwork in vivo due to each specific role within ovarian physiology.

FSH induces the development of circadian clockwork in rat granulosa cells via a gap junction protein Cx43-dependent pathway

“…We concluded that circadian clockwork in ovarian cells is affected during cellular differentiation. Another study illustrated that both follicle-stimulating hormone (FSH) and LH exerted diverse specific functions on the clockwork of granulosa cells in vitro as proved by Per2 oscillations (25). Consistent with the above two reports (24,25), a study demonstrated that endocrine signals, FSH, and LH are able to transmit phase information to the ovaries and cultured ovarian cells in vivo and in vitro (72).…”

“…Over the past decade, accumulating evidence has demonstrated that functional circadian clockwork exists in mammalian ovaries (8,11,12,16,25,31,42,52,72). Originally, Fahrenkrug et al (16) showed that rat ovaries displayed a circadian expression of the clock genes Period (Per) 1 and Per2.…”

Hormonal Regulation of Circadian Pacemaker in Ovary and Uterus

“…2, B & C). Conversely, a few robust oscillations were detected in the granulosa cells from antral follicles, albeit with a continuous decreasing of amplitude (He et al, 2007a). FSH was also effective at inducing the oscillation seen at approximately 24 h (Fig.…”

“…The circadian clock system may contribute to the progress of follicular development, luteinization and luteolysis, and steroid hormone-induced proliferation and differentiation of uterine cells through fluctuating hormones. Recently, there is a growing body of evidence that circadian clock genes are expressed in reproductive tissues including the ovary and uterus (Johnson et al, 2005;Nakamura et al, 2005;Fahrenkrug et al, 2006;Dolatshad et al, 2006;Karman & Tischkau, 2006;He et al, 2007aHe et al, , 2007bHe et al, , 2007cNakao et al, 2007;Hirata et al, 2009;Sellix & Menaker, 2010;Uchikawa et al, 2011). Many regulatory elements are located at the upstream of clock genes, such as steroid hormone response element half-sites and the adenosine 3',5'-cyclic monophosphate (cAMP) response element site as well as E-box and D-box elements.…”

Biological rhythms and fertility: the hypothalamus–pituitary–ovary axis

“…52 The same study provided evidence for a gonado tropinmediated regulation of clock gene expression in the ovaries, as FSH acutely induced Per1 expression in granulosa cells in vitro with a peak within 1 hour. A similar induction was found after the administration of LH in mature granulosa cells, and both FSH and LH seemed to be able to synchronize the circadian rhythm in granulosa cells.…”