Elucidation of the physiological roles of Hippo signalling in bovine ovarian follicle cells

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Hippo is an evolutionarily conserved signaling pathway with established roles in cell differentiation, proliferation and apoptosis in a variety of tissues during embryogenesis. The core Hippo pathway consists of a kinase cascade that negatively regulates the activity of the transcriptional activators yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). Although recent studies in humans and rodents have linked the Hippo signaling to primary ovarian insufficiency in women, there are no studies showing the roles of Hippo signaling in ovarian physiology and/or pathophysiology of species of agricultural importance, as the cow. Therefore, we will investigate this pathway in the bovine ovarian follicle. Our preliminary results indicated that key Hippo signaling effectors, YAP/TAZ, are regulated by the luteinizing hormone (LH) in bovine preovulatory granulosa cells. We, therefore, hypothesized that LH activates Hippo signaling in bovine granulosa cells and that it requires YAP and TAZ to exert its effects on luteinization, cumulus cell-oocyte complex expansion and ovulation. To confirm this, we will use in vitro and in vivo bovine models. Experiments will be also required to determine if follicle-stimulating hormone (FSH) modulates Hippo effectors expression and activity in bovine granulosa cells, for what purpose and if this is relevant to bovine follicle growth. The main focus for my research program is to determine the relevance of key Hippo signaling effectors throughout follicle development in cows. The short-term objectives of this proposal are 1) to elucidate the involvement of Hippo signaling in the ovulatory cascade, 2) to elucidate the involvement of Hippo signaling effectors in follicle development, and 3) to determine the mechanisms of Hippo action in bovine granulosa cells. Together, the proposed studies in cattle will provide, for the first time, considerable insight into the regulation, physiological roles and mechanisms of action of a completely novel signaling pathway during ovarian follicle growth and ovulation in this species. These findings may lead to applications for the manipulation of Hippo signaling in vivo, such as the pharmacological targeting of specific signaling pathway effectors, that may result in industry funding to better use the ovarian follicle reserve in high genetic merit animals superovulated for in vitro embryo production. This is a major economic activity in the Canadian dairy industry with over 12,000 embryos being exported to over 30 countries in 2016, creating trade worth more than $8 million.