The roles of Hippo signaling pathway in mouse ovarian function

Mammalian follicular development is regulated by various secreted and gap-junction-mediated intercellular communication signals. This complicated network of regulatory and metabolic mechanisms is not completely known. The Hippo signaling pathway has been recognized as a highly conserved pathway among species that controls the organ size, stem cell functions and is also profoundly implicated in numerous human cancers and other diseases. Lats1 mutant mice exhibit follicle depletion and develop ovarian stromal tumors, while its effector YAP1 is not only recognized as an ovarian oncoprotein, but also found to promote follicular growth when actin polymerization is initiated by ovarian physical disruption. These studies demonstrated the potential importance of Hippo signaling in ovarian function, but little is known about what roles this pathway plays during early follicular development and ovulation. Our study first utilized Lats1 mutant mice and the YAP1 inhibitor verteporfin to study the roles of Hippo pathway in early follicular development and found that LATS1 is required for maintaining the primordial germ cell pool and both LATS1 and YAP1 are essential for follicle activation. Then we established a new mechanistic model for the regulation of ovulation, by demonstrating that oocytes induce granulosa cell proliferation by inhibiting the expression of Hippo components before ovulation, while ovulatory signals promote granulosa cell differentiation by activating the Hippo signaling activity in a timely manner during ovulation. Lastly, we accentuated the importance of Hippo pathway during ovulation by showing that blocking YAP1 leads to spindle deformation during oocyte maturation. More importantly, pYAP1 at T119 site is induced through meiotic progression and was shown to be a target of PP2A phosphatase. However, it's unclear if this regulation of pYAP1 plays important roles in actin cytoskeleton-mediated spindle assembly and migration during oocyte meiosis. Together, our findings contributed to our understanding of the impact of Hippo pathway in early follicular development and how it mediates the ovulatory transition in cumulus granulosa cells and oocytes.