Molecular physiology of follicular development and ovulation

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Dairy cows fertility has been declining steadily worldwide for the last fifty years. This decline in fertility is a major concern for the dairy industry in Canada since it results in significant economic losses each year. Yet, the molecular mechanisms associated with fertility decline are still not fully investigated. Although the causes associated with fertility decline are various, they often involve the ovary and a well-coordinated regulation of specific genes. The essential regulation of Janus kinase 3 (JAK3) and Ankyrin-repeat and SOCS Box protein 9 (ASB9) in the ovarian follicle has been recently reported, for the first time, by my laboratory. The luteinizing hormone (LH) downregulates JAK3 in ovarian granulosa cells (GC) while inducing ASB9 prior to ovulation from in vivo experiments. However, the biological roles of JAK3 and ASB9 signaling pathways in follicle growth and ovulation are unknown. Our long-term goal is to dissect the molecular mechanisms that regulate the ovarian function in the bovine species, particularly in the setting of dairy cows declining fertility. The emphasis of this research program will be on the cellular signals of target genes that affect GC proliferation, differentiation and function. These studies will lead to the acquisition of fundamental knowledge regarding the molecular physiology of the ovary and the identification of potential markers to enhance bovine fertility. The objective of this proposal is to uncover the precise functions of JAK3 and ASB9 in ovarian GC and the impacts of their signaling in the developing follicle and ovulation, respectively. The central hypothesis is that JAK3 and ASB9 play pivotal roles in the late stages of follicular growth and in ovulation and that disruption of their signaling would contribute to reproductive efficiency decline. Our rationale is that the identification of the exact mechanisms of action of these genes in GC will lead to new and innovative ways to regulate the ovary. Our specific objectives will test the following hypotheses: 1) Final stages of follicular growth require the activation of JAK3 pathway in GC; and 2) Induction of ASB9 by LH and activation of ASB9 signaling is critical for the ovulation process. Upon completion, these investigations will unveil new signaling pathways and mechanisms of regulation of GC function and increase our understanding of bovine reproductive challenges. This research program is a significant contribution since it will determine target proteins for JAK3 and ASB9 that regulate the ovarian activity. It is an innovative research program since it aims to study the impacts of signaling pathways of two candidate genes whose functions in GC have not been examined before. Insight into GC regulation is impactful as candidate genes associated with dairy cows' fertility can be identified and used as molecular markers for healthy oocytes leading to reduced economic losses for the dairy industry.