Hippo Signaling in the Ovary: Emerging Roles in Development, Fertility, and Disease

Abstract

Emerging studies indicate that the Hippo pathway, a highly conserved pathway that regulates organ size control, plays an important role in governing ovarian physiology, fertility, and pathology. Specific to the ovary, the spatiotemporal expression of the major components of the Hippo signaling cascade are observed throughout the reproductive lifespan. Observations from multiple species begin to elucidate the functional diversity and molecular mechanisms of Hippo signaling in the ovary in addition to the identification of interactions with other signaling pathways and responses to various external stimuli. Hippo pathway components are important for follicle growth and activation, as well as steroidogenesis by regulating several key biological processes through mechanisms of cell proliferation, migration, differentiation, and cell fate determination. Given the importance of these processes, dysregulation of the Hippo pathway contributes to loss of follicular homeostasis and reproductive disorders such as polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), and ovarian cancers. This review highlights what is currently known about the Hippo pathway core components in ovarian physiology including ovarian development, follicle development, and oocyte maturation while identifying areas for future research to better understand Hippo signaling as a multifunctional pathway in reproductive health and biology.

FHL2 deficiency impairs follicular development and fertility by attenuating EGF/EGFR/YAP signaling in ovarian granulosa cells

“…Our very recent published paper reviewed that the highly conserved Hippo pathway, especially its downstream effector YAP1, plays a critical role in governing ovarian physiology, fertility, and pathology [ 22 ]. Similar with the subfertile phenotype observed in Fhl2 KO mice, our previous study proved that Foxl2 promoter-driven knockout of Yap1 in ovarian GCs also increased GCs apoptosis, disrupted follicular development and impaired fertility [ 23 ].…”

A Biomimetic Follicle‐Based Design for Engineering Reproductive Technologies

“…[52] The transcriptional co-activator YAP1 is a primary downstream effector of the cascade. [52] Its activity is regulated by upstream regulators MST2 and TEAD4, [53] which ultimately govern cell fate, growth, and proliferation. [54,55] Here, we observed the upregulation of YAP1, MST2, and TEAD4 mRNA transcripts in COCs matured in vitro in the bilayer hydrogel system compared to the 2D Control (Figure 6C; p < 0.05).…”

The Effect of Stimulation Protocols (GnRH Agonist vs. Antagonist) on the Activity of mTOR and Hippo Pathways of Ovarian Granulosa Cells and Its Potential Correlation with the Outcomes of In Vitro Fertilization: A Hypothesis

“…The Hippo pathway is mediated by the phosphorylation of the mammalian sterile 20-related kinases 1 and 2 (Mst1/2), which activate the large tumor suppressor kinases 1 and 2 (Lats1/2). The latter, phosphorylate the translation activators YAP-1 and TAZ, which thus remain outside the nucleus and are degraded in the cytoplasm [ 46 , 47 , 48 ]. Hippo is inhibited during ovarian stimulation through cytoskeletal reorganization, extracellular matrix stiffness, ovarian fragmentation, and the activation of G protein-coupled receptors, integrins, or growth factors [ 46 , 49 ].…”

“…The latter, phosphorylate the translation activators YAP-1 and TAZ, which thus remain outside the nucleus and are degraded in the cytoplasm [ 46 , 47 , 48 ]. Hippo is inhibited during ovarian stimulation through cytoskeletal reorganization, extracellular matrix stiffness, ovarian fragmentation, and the activation of G protein-coupled receptors, integrins, or growth factors [ 46 , 49 ]. Thus, the unphosphorylated YAP-1 and TAZ activators freely enter the nucleus, form complexes with TEA domain family member transcription factors (TEADs), and further stimulate the transcription of proliferation-related and growth factor genes [ 47 , 48 , 50 ].…”

“…The Hippo pathway effectors interact with the EGF-like signaling [ 51 ], as well as the components of the aforementioned intracellular signaling involving mTOR [ 12 , 14 , 52 ]. Excessive inhibition of the Hippo pathway and unrestrained inflow of the chief final mediators YAP-1 and TAZ into the nucleus have been involved in the development of PCOS [ 46 , 53 ], endometriosis [ 54 , 55 ], and ovarian tumorigenesis [ 56 ]. On the other hand, in vitro fragmentation and controlled inhibition of Hippo (combined with administration of PI3K/Akt/mTOR activators) can promote the growth of preantral follicles in patients with primary ovarian insufficiency [ 57 , 58 , 59 ].…”