Role of OCT4 in the Regulation of FSH-Induced Granulosa Cells Growth in Female Mice

Dai, Hancheng; Wang, Qiaozhi; Ma, Xiaoshu; Tian, Ye; Xu, Kaili; Weng, Xuechun; Hu, Xusong; Liu, Wenbo; Zhang, Cheng

doi:10.3389/fendo.2019.00915

Cited by 17 publications

(11 citation statements)

References 42 publications

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“…Recently, a study in mice showed that FSH can be involved in ovarian cell development through the regulation of OCT4 expression in granulosa cells at the preantral to early antral transition stage of follicles via the glycogen synthase kinase (GSK)-3β/β-catenin pathway, and this response was found to be mediated by the phosphoinositide 3-kinases/serine/threonine kinase (PI3K/Akt) signaling pathway [ 172 ]. In many species, GCs from preantral (at the secondary follicle stage) and antral follicles at different stages of follicular growth were shown to express FSHR [ 126 , 127 , 128 ].…”

Section: Influence Of Fsh On Germ Cellsmentioning

confidence: 99%

Actions and Roles of FSH in Germinative Cells

Recchia

Jorge

Pessôa

et al. 2021

IJMS

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Follicle stimulating hormone (FSH) is produced by the pituitary gland in a coordinated hypothalamic–pituitary–gonadal (HPG) axis event, plays important roles in reproduction and germ cell development during different phases of reproductive development (fetal, neonatal, puberty, and adult life), and is consequently essential for fertility. FSH is a heterodimeric glycoprotein hormone of two dissociable subunits, α and β. The FSH β-subunit (FSHβ) function starts upon coupling to its specific receptor: follicle-stimulating hormone receptor (FSHR). FSHRs are localized mainly on the surface of target cells on the testis and ovary (granulosa and Sertoli cells) and have recently been found in testicular stem cells and extra-gonadal tissue. Several reproduction disorders are associated with absent or low FSH secretion, with mutation of the FSH β-subunit or the FSH receptor, and/or its signaling pathways. However, the influence of FSH on germ cells is still poorly understood; some studies have suggested that this hormone also plays a determinant role in the self-renewal of germinative cells and acts to increase undifferentiated spermatogonia proliferation. In addition, in vitro, together with other factors, it assists the process of differentiation of primordial germ cells (PGCLCs) into gametes (oocyte-like and SSCLCs). In this review, we describe relevant research on the influence of FSH on spermatogenesis and folliculogenesis, mainly in the germ cell of humans and other species. The possible roles of FSH in germ cell generation in vitro are also presented.

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Section: Influence Of Fsh On Germ Cellsmentioning

confidence: 99%

Actions and Roles of FSH in Germinative Cells

Recchia

Jorge

Pessôa

et al. 2021

IJMS

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“…In line with the predicted results of network pharmacology, we detected a remarkably decreased level of GSK3β (Tyr216) and increased level GSK3β (Ser9) of in KXS-treated group, which indicated a significant inhibition of GSK3β activation. The best studied mechanism by which GSK3β is regulated is Akt-dependent serine phosphorylation [ 51 ]. AKT phosphorylates GSK3β at the S9 residue, which inactivates GSK3β [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Kai-Xin-San Inhibits Tau Pathology and Neuronal Apoptosis in Aged SAMP8 Mice

et al. 2022

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Alzheimer’s disease (AD) is an age-related neurological disorder. Currently, there is no effective cure for AD due to its complexity in pathogenesis. In light of the complex pathogenesis of AD, the traditional Chinese medicine (TCM) formula Kai-Xin-San (KXS), which was used for amnesia treatment, has been proved to improve cognitive function in AD animal models. However, the active ingredients and the mechanism of KXS have not yet been clearly elucidated. In this study, network pharmacology analysis predicts that KXS yields 168 candidate compounds acting on 863 potential targets, 30 of which are associated with AD. Enrichment analysis revealed that the therapeutic mechanisms of KXS for AD are associated with the inhibition of Tau protein hyperphosphorylation, inflammation, and apoptosis. Therefore, we chose 7-month-old senescence-accelerated mouse prone 8 (SAMP8) mice as AD mouse model, which harbors the behavioral and pathological hallmarks of AD. Subsequently, the potential underlying action mechanisms of KXS on AD predicted by the network pharmacology analyses were experimentally validated in SAMP8 mice after intragastric administration of KXS for 3 months. We observed that KXS upregulated AKT phosphorylation, suppressed GSK3β and CDK5 activation, and inhibited the TLR4/MyD88/NF-κB signaling pathway to attenuate Tau hyperphosphorylation and neuroinflammation, thus suppressing neuronal apoptosis and improving the cognitive impairment of aged SAMP8 mice. Taken together, our findings reveal a multi-component and multi-target therapeutic mechanism of KXS for attenuating the progression of AD, contributing to the future development of TCM modernization, including KXS, and broader clinical application. Graphical abstract

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“…However, this study still has some limitations including our use of KGN cells as a TRIB3 gene knockdown model. Although the KGN cell line is more likely to be closer to granulosa cells in normal physiological conditions than other human cell lines [39], additional studies are warranted because this model does not completely replicate the physiological environment of the human body. Furthermore, the TRIB3 effect on the granulosa cells or even on the folliculogenesis in conditional TRIB3 gene knockout mouse model also needs further study.…”

Section: Discussionmentioning

confidence: 99%

TRIB3 regulates FSHR expression in human granulosa cells under high levels of free fatty acids

Wang

Xia

et al. 2021

Reprod Biol Endocrinol

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Background Granulosa cells (GCs) in cumulus oophorus highly express follicle stimulating hormone receptor (FSHR), which is the most important mediator of both estradiol synthesis and oocyte maturation. Obese women have elevated free fatty acids (FFAs) levels in their follicular fluids and decreased FSHR expression in GCs, which is related to an altered protein kinase B/glycogen synthase kinase 3β (Akt/GSK3β) signaling pathway. Such FFA increases accompany 3-fold rises in pseudokinase 3 (TRIB3) expression and reduce the Akt phosphorylation status in both the human liver and in insulinoma cell lines. Therefore, in a high FFA environment, we determined if TRIB3 mediates regulation of FSHR via the Akt/GSK3β signaling pathway in human GCs. Methods GCs from women undergoing in vitro fertilization were collected and designated as high and low FFAs cohorts based on their follicular fluid FFA content. GCs with low FFA levels and a human granulosa-like tumor (KGN) cell line were exposed to palmitic acid (PA), which is a dominate FFA follicular fluid constituent. The effects were assessed of this substitution on the Akt/GSK3β signaling pathway activity as well as the expressions of TRIB3 and FSHR at both the gene and protein levels by qPCR, Western blot and immunofluorescence staining analyses. Meanwhile, the individual effects of TRIB3 knockdown in KGN cells and p-AKT inhibitors were compared to determine the mechanisms of FFA-induced FSHR downregulation. Results The average FSH dose consuming per oocyte (FSH dose/oocyte) was elevated and Top embryo quality ratio was decreased in women with high levels of FFAs in their follicular fluid. In these women, the GC TRIB3 and ATF4 protein expression levels were upregulated which was accompanied by FSHR downregulation. Such upregulation was confirmed based on corresponding increases in their gene expression levels. On the other hand, the levels of p-Akt decreased while p-GSK3β increased in the GCs. Moreover, TRIB3 knockdown reversed declines in FSHR expression and estradiol (E2) production in KGN cells treated with PA, which also resulted in increased p-Akt levels and declines in the p-GSK3β level. In contrast, treatment of TRIB3-knockdown cells with an inhibitor of p-Akt (Ser473) resulted in rises in the levels of both p-GSK3β as well as FSHR expression whereas E2 synthesis fell. Conclusions During exposure to a high FFA content, TRIB3 can reduce FSHR expression through stimulation of the Akt/GSK3β pathway in human GCs. This response may contribute to inducing oocyte maturation.

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Role of OCT4 in the Regulation of FSH-Induced Granulosa Cells Growth in Female Mice

Cited by 17 publications

References 42 publications

Actions and Roles of FSH in Germinative Cells

Actions and Roles of FSH in Germinative Cells

Kai-Xin-San Inhibits Tau Pathology and Neuronal Apoptosis in Aged SAMP8 Mice

TRIB3 regulates FSHR expression in human granulosa cells under high levels of free fatty acids

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