β-Catenin directs the transformation of testis Sertoli cells to ovarian granulosa-like cells by inducing Foxl2 expression

Li, Yaqiong; Zhang, Lianjun; Hu, Yuqiong; Han, Feng; Qin, Yan; Chen, Min; Cui, Xiuhong; Duo, Shuguang; Tang, Fuchou; Gao, Fei

doi:10.1074/jbc.m117.811349

Cited by 35 publications

(40 citation statements)

References 35 publications

(42 reference statements)

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“…The expression of β-catenin and Bcl-2 as signals of the WNT signaling pathway was determined due to their relationship with folliculogenesis. β-Catenin regulates GC differentiation, and its over-activation leads to a Sertoli-to-granulosa-like cell transformation 40. Bcl-2 overexpression increases the number of primordial follicles 41, while its downregulation is involved in GC apoptosis which was induced by autophagosome accumulation 42.…”

Section: Discussionmentioning

confidence: 99%

NFAT5 is Regulated by p53/miR-27a Signal Axis and Promotes Mouse Ovarian Granulosa Cells Proliferation

Tao¹,

Xiong²,

Ji³

et al. 2019

Int. J. Biol. Sci.

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MicroRNAs (miRNAs) play key roles in mammalian folliculogenesis (a complex process in which primordial follicles develop into mature oocytes) by inhibiting mRNA translation or by inducing its degradation, while the role of miRNA in folliculogenesis and regulation mechanism remain unclear. In this study, we explored the role of the p53/miR-27a/nuclear factor of activated T-cells 5 (NFAT5) signaling axis in mouse ovarian granulosa cell proliferation. Luciferase reporter assay, overexpression, site-directed mutagenesis, and chromatin immunoprecipitation (ChIP) assay results showed that the transcription factor p53 significantly decreased the expression level of miR-27a by binding to sites 4 (-646 to -637 bp) and 10 (-50 to -41 bp) of the miR-27a promoter. Moreover, miR-27a directly targeted the 3′-untranslated region of the target gene, NFAT5, to regulate its expression levels. p53 also upregulated the expression of NFAT5. Meanwhile, overexpression of NFAT5 strongly upregulated the mRNA and protein levels of the Wnt signaling genes, β-catenin and B-Cell CLL/Lymphoma 2 (Bcl-2). In addition, NFAT5 promoted mouse granulosa cell proliferation; this was confirmed by EdU/Hoechst immunostaining. Taken together, our findings define a novel pathway p53/miR-27a/NFAT5, and NFAT5 regulates mouse granulosa cell functions via activating Wnt signaling pathway.

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Section: Discussionmentioning

confidence: 99%

NFAT5 is Regulated by p53/miR-27a Signal Axis and Promotes Mouse Ovarian Granulosa Cells Proliferation

Tao¹,

Xiong²,

Ji³

et al. 2019

Int. J. Biol. Sci.

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“…Our previous studies have demonstrated that over-activation of Ctnnb1 by deletion of exon 3 results in testicular cord disruption and Sertoli to granulosa-like cells transformation (Chang et al, 2008; Li et al, 2017). To track the differentiation of germ cells in Ctnnb1 +/flox(ex3) AMH-Cre mice (hereafter referred as COA mice unless otherwise specified), the expression of germ cell specific and meiosis-associated genes was analyzed by immunofluorescence and quantitative RT-PCR.…”

Section: Resultsmentioning

confidence: 99%

“…Control and CTNNB1 over-activated Sertoli cells from ROSA mT/mG AMH-Cre and Ctnnb1 +/flox(ex3) ROSA mT/mG AMH-Cre mice at E13.5 and E14.5 were isolated using flow cytometry based on GFP fluorescence as described previously (Li et al, 2017). The sorted cells were stored at −80°C for RNA extraction.…”

Section: Methodsmentioning

confidence: 99%

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Somatic cell-derived BMPs induce male germ cell meiosis initiation during embryonic stage via regulatingDazlexpression

Zhang

et al. 2020

Preprint

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Germ cell fate is believed to be determined by the signaling from sexually differentiated somatic cell. However, the molecular mechanism remains elusive. In this study, ectopic initiation of meiosis in male germ cells was observed during embryonic stage by over-activating CTNNB1 in Sertoli cells. Somatic cell transcriptome and single germ cell RNA-seq analysis indicated that TGF-β signaling was activated after CTNNB1 over-activation. In vitro and in vivo experiments confirmed somatic cell-derived BMPs played crucial roles in germ cell meiosis initiation. Further studies revealed that Dazl was significantly increased in germ cells of CTNNB1 over-activated testes and induced by BMP signaling. DNMT3a and DNA methylation was also reduced in germ cells of CTNNB1 over-activated testes and increased by BMP signaling inhibitor treatment. Taken together, this study demonstrates that germ cell fate could be reprogrammed after sex determination. BMP signaling pathway is involved in germ cell meiosis initiation via up-regulating Dazl expression.

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“…Elegant reviews on molecular pathogenesis, signaling pathways and mouse models of ovarian GCTs have been published (4,40,41). The present review focuses on several mouse models that have been reported to develop testicular tumors with a sex cord-stromal origin (12,18,19,(42)(43)(44). Inhibins and activins are key regulators of ovarian development and function.…”

Section: Genetically Modified Mouse Models To Study Tgctsmentioning

confidence: 99%

New insights into testicular granulosa cell tumors (Review)

Fang

2020

Oncol Lett

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Testicular granulosa cell tumors (TGCTs) are rare tumors of sex cord-stromal origin. TGCTs are mostly benign and can be classified into the adult type and the juvenile type. Due to the rarity of clinical cases and limited research efforts, the mechanism underpinning the development of TGCTs remains poorly understood. A landmark study has identified a forkhead box L2 mutation (C134W) in nearly all adult ovarian GCTs, but its implications in TGCTs are unclear. The present study focuses on reviewing the major signaling pathways (e.g., the transforming growth factor β signaling pathway) critical for the development of TGCTs, as revealed by genetically modified mouse models, with a goal of providing new insights into the pathogenesis of TGCTs and offering directions for future studies in this area. We posit that a comparative approach between testicular and ovarian GCTs is valuable, as granulosa cells and Sertoli cells arise from the same progenitor cells during gonadal development. Developing pre-clinical mouse models that recapitulate TGCTs will help answer the remaining questions around this type of rare tumor. Contents 1. Introduction 2. Tumors in the testes 3. TGCTs: Subtypes and histopathology 4. FOXL2 mutation in GCT development 5. Genetically modified mouse models to study TGCTs 6. Concluding remarks and future directions

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β-Catenin directs the transformation of testis Sertoli cells to ovarian granulosa-like cells by inducing Foxl2 expression

Cited by 35 publications

References 35 publications

NFAT5 is Regulated by p53/miR-27a Signal Axis and Promotes Mouse Ovarian Granulosa Cells Proliferation

NFAT5 is Regulated by p53/miR-27a Signal Axis and Promotes Mouse Ovarian Granulosa Cells Proliferation

Somatic cell-derived BMPs induce male germ cell meiosis initiation during embryonic stage via regulatingDazlexpression

New insights into testicular granulosa cell tumors (Review)

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