Hippo Signaling Pathway Reveals a Spatio-Temporal Correlation with the Size of Primordial Follicle Pool in Mice

Abstract

Background: The Hippo signaling pathway, a highly conserved cell signaling system, exists in most multicellular organisms and regulates cell proliferation, differentiation, and apoptosis. It has been reported that the members of Hippo signaling are expressed in mammalian ovaries, but the exact functions of this pathway in primordial follicle development remains unclear. Methods: To analyze the spatio-temporal correlation between the core component of Hippo pathway and the size of primordial follicle pool, Western blot, Real-time PCR and immunohistochemistry were used, and the expression and localization of MST1, LATS2 and YAP1 mRNA and protein were examined in 3 d, 1 m, 5 m, 16 m postnatal mice ovary and the culture model of mice primordial follicle in vitro. Results: Both the protein and mRNA expression of the MST1 and LATS2 were decreased significantly as mouse age increased (p < 0.05), however, the mRNA expression of them increased significantly in 16 m compared with 5 m as well as the protein expression of LATS2.The expression of YAP showed the opposite trend, and the significant protein expression of pYAP was increased before 1 m, after which no significant change was observed. Moreover, the ratio of pYAP/YAP decreased significantly. Culturing ovaries for 8 d in vitro resulted in the activation of primordial follicles in 3 d postnatal mice ovaries, and these developed into primary follicles with the expression of PCNA increasing significantly (p < 0.05). The mRNA and protein expression of MST and LATS decreased significantly (p < 0.05), and the expression of YAP increased significantly (p < 0.05, p < 0.01), whereas the ratio of pYAP/YAP decreased significantly (p < 0.05). Conclusion: The above results reveal that the expression of the core components of Hippo pathway changed during mouse follicular development, especially before and after primordial follicle activation in vitro. The primordial follicle activation may be related to the significant decrease of the ratio of pYAP1/YAP1. In conclusion, Hippo signaling pathway expressed in mice ovaries and have spatio-temporal correlation with the size of primordial follicle pool.

Ovarian Germline Stem Cells (OGSCs) and the Hippo Signaling Pathway Association with Physiological and Pathological Ovarian Aging in Mice

“…Our recent results revealed that the Hippo signaling pathway is expressed in mouse ovaries and the expression of the core components of the Hippo pathway change during mouse follicular development [42]. In this study, as seen in Fig.…”

“…Previous studies have shown that the Hippo signaling pathway forms a cross network with a variety of factors and multiple signaling pathways such as Notch, TGFβ, c-myc, and PI3K/AKt, which are crucial for the self-renewal and differentiation of stem cells [22,36,37,38,39]. Importantly, several lines of our evidence suggest that the upstream activation of Notch signaling pathways, which have been proven to play a role in germ-line stem cells in ovaries [40,41], and the Hippo signaling pathway have a spatio-temporal correlation with the size of the primordial follicle pool [42]. Hence, the aim of this study is to reflect the variation in the number of OGSCs and explore the expression changes of the core components of the Hippo pathway (MST1, LATS2, YAP1) during physiological aging and pathological aging of OGSCs in the mice OSE layers.…”

The Hippo Signaling Pathway Regulates Ovarian Function via the Proliferation of Ovarian Germline Stem Cells

“…In addition, the OSE layer has cell-cell contacts and local signaling that may be associated with GSC growth and development [22]. Importantly, evidence suggests that the Hippo signaling pathway is spatiotemporally correlated with the size of the primordial follicle pool [23] and that the existence of OGSCs in the mouse OSE and the expression of OGSCs markers are correlated with both the age of the mouse and with Hippo signaling molecules [24]. …”

Ovarian Physiology and GWAS: Biobanks, Biology, and Beyond

“…Notably, this provides evidence the Erb-B pathway might be implicated in PCOS, and this pathway is involved in primordial germ cell development in mice [63]. In addition, ERBB3 interacts with YAP1 in the Hippo pathway, which regulates organ size by controlling cell proliferation and apoptosis, and has been associated with primordial follicle pool in mice [64]. Taken together, these five studies provide considerable evidence for the role of the Hippo pathway, neuroendocrine changes (mediated by LHCGR, FSHR and FSHB), and EGFRs in PCOS pathophysiology.…”