Mechanism of action of Hippo effectors in the regulation of the cascade of pre-ovulatory events in cattle

• Grant number: 19/15491-6
• Support Opportunities: Regular Research Grants
• Start date: January 01, 2020
• End date: December 31, 2022
• Field of knowledge: Agronomical Sciences - Veterinary Medicine - Animal Reproduction
• Agreement: Comisión Nacional de Investigación Científica y Tecnológica (CONICYT)
• Principal Investigator: Flávio Vieira Meirelles
• Grantee: Flávio Vieira Meirelles
• Host Institution: Faculdade de Zootecnia e Engenharia de Alimentos (FZEA). Universidade de São Paulo (USP). Pirassununga , SP, Brazil
• Associated researchers: Fabiana Fernandes Bressan ; Felipe Perecin ; Juliano Coelho da Silveira ; Valério Valdetar Marques Portela Junior

Abstract

In humans and animals, control of ovulation, low oocyte fertility, occurrence of ovarian tumors, and development of polycystic ovaries or ovarian cysts are problems that need to be elucidated. The physiological and molecular knowledge of the mechanisms related to follicular growth, ovulation and oocyte competence are fundamental for the development of biotechnologies that contribute to the solution of these and other problems related to the ovulatory process. The understanding of the cascade of events in preovulatory follicles beginning at the ovulatory peak of the luteinizing hormone (LH) and culminating in follicular wall rupture and the release of a cumulus-oocyte complex capable of being fertilized are essential in assisted reproduction and biotechnological processes. Over the last few years, the cascade of intrafollicular events induced by the peak of LH has been elucidated, mainly in relation to the expression of prostaglandin synthase 2 (PTGS2) and the involvement of factors similar to the epidermal growth factor (EGF-like factors): ampiregulin (AREG) and epiregulin (EREG). These factors were identified as genes rapidly induced by LH in granulosa cells and by EGF in cumulus cells. Recent studies have indicated that the Hippo signaling pathway plays an important role in the expression of AREG, EREG and PTGS2 in different tissues and that the deregulation of YAP (yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif ), effectors of the Hippo pathway, are directly associated with ovarian disorders that result in anovulation. In addition, other recent studies have demonstrated the association of the PI3K / AKT signaling pathway with oocyte competence, which, among other activities, measured YAP / TAZ translocation to the nucleus. Therefore, this project proposes the investigation of the participation of the effectors of the Hippo cell signaling pathway and its relation with PI3K / AKT in the control of the cascade of intrafollicular events that coordinate the ovulatory process and in the control of events that modulate oocyte quality in cattle . Thus, in vitro and in vivo experiments are being proposed with the objective of investigating the participation of the Hippo cell signaling mechanism and its relation to the PI3K / AKT pathway in ovulation induction and in the acquisition of oocyte competence. For that, three experimental models were developed by our groups. An in vitro model with cultured granulosa cells from dominant 10 to 14 mm diameter follicles, which express the genes essential for ovulation control in response to LH; an ex vivo model, using ovarian culture; and an in vivo model, modifying the follicular environment by intrafollicular injection guided by ultrasound. Experimenting with these models we hope to understand mechanisms involved in ovulation processes and acquisition of oocyte competence, identifying the role of the effectors of the Hippo cell signaling pathway and its relation to the AKT enzyme and mechanisms of cell proliferation. This knowledge should be the basis for a better understanding of cellular processes related to ovulation control, oocyte competence and the development of ovarian tumors and cysts in animals and humans. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DA SILVEIRA, JULIANO COELHO; ANDRADE, GABRIELLA MAMEDE; SIMAS, ROSINEIDE COSTA; MARTINS-JUNIOR, HELIO ALVES; EBERLIN, MARCOS NOGUEIRA; SMITH, LAWRENCE CHARLES; PERECIN, FELIPE; MEIRELLES, FLAVIO VIEIRA. Lipid profile of extracellular vesicles and their relationship with bovine oocyte developmental competence: New players in intra follicular cell communication. Theriogenology, v. 174, p. 1-8, OCT 15 2021. (11/15416-2, 19/15491-6, 15/21829-9, 12/50533-2, 13/08135-2, 14/22887-0, 14/21034-3)