Cell signaling in ovarian function

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The cell is the unit of life. A cell functions as a single entity or as part of a group. The appropriate response of a cell to its environment is of great importance, not only for cell's survival, but for performing a physiological role. The cell's response to hormonal stimulation involves signal transduction which often includes cyclic nucleotides as key players. In recent decades, cyclic adenosine monophosphate (cAMP) has become much more studied than cyclic guanosine monophosphate (cGMP). In the ovary, the contribution of cAMP has been characterized in response to follicle-stimulating hormone (FSH), luteinizing hormone (LH), and studied in steroidogenesis, but what about the role of cGMP in the cells of ovarian follicles? Over the past few years, the contribution of cGMP has gained more attention because of the inhibitory model of oocyte meiotic resumption in mammals. This model suggests that the cGMP is synthesized mainly by the granulosa and cumulus cells in response to the C-type natriuretic peptide. The electrophysiological syncytium created between granulosa cells, cumulus cells and the oocyte by gap junctions allows cGMP to diffuse from the granulosa cells to the oocyte, and consequently inhibits oocyte phosphodiesterase. This enzymatic inhibition increases intra-oocyte cAMP that blocks meiotic resumption. However, very little is known about the role of cGMP in ovarian follicles. It is unlikely that cGMP is only waiting to move to the oocyte. What does cGMP target? What are the physiological impacts of cGMP? Does cGMP modulate cAMP response?***The long-term objective of the proposed research program is to refine our understanding of the importance of signal transduction in the different physiological responses of the ovarian follicles. Since cAMP mediates FSH and LH responses such as cellular differentiation, the hypothesis is that cGMP plays a major physiological role as a second messenger, possibly modulating the cellular differentiation of the electrophysiological syncytium. Therefore, aside from the role of cGMP in the inhibition of oocyte meiotic resumption, what is its physiological contribution within the cells of the ovarian follicle? The short-term objectives are to 1) characterize the molecular machinery involved in cGMP signaling by comparing three follicular stages; 2) to identify cGMP targets by studying the phosphoproteome; and 3) to demonstrate the physiological involvement of cGMP in mediating ovarian functions using chemical agonists and inhibitors.***This research program represents a major contribution to the current knowledge about improving oocyte quality during in-vitro maturation. This will impact the development of new reproductive biotechnology related to the quality of the female gamete, as well as lead to genetic improvements sought after by the pork industry. Finally, this research program assesses fundamental signaling which also has beneficial applications to other species such as dairy cattle.