| catenin beta 1 | OKDB#: 930 |
| Symbols: | CTNNB1 | Species: | human | ||
| Synonyms: | EVR7, CTNNB, MRD19, NEDSDV, armadillo | Locus: | 3p22.1 in Homo sapiens |
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| General Comment |
Arrest of WNT/β-catenin signaling enables the transition from pluripotent to differentiated germ cells in mouse ovaries. Le Rolle M et al. (2021) Germ cells form the basis for sexual reproduction by producing gametes. In ovaries, primordial germ cells exit the cell cycle and the pluripotency-associated state, differentiate into oogonia, and initiate meiosis. Despite the importance of germ cell differentiation for sexual reproduction, signaling pathways regulating their fate remain largely unknown. Here, we show in mouse embryonic ovaries that germ cell-intrinsic β-catenin activity maintains pluripotency and that its repression is essential to allow differentiation and meiosis entry in a timely manner. Accordingly, in β-catenin loss-of-function and gain-of-function mouse models, the germ cells precociously enter meiosis or remain in the pluripotent state, respectively. We further show that interaction of β-catenin and the pluripotent-associated factor POU5F1 in the nucleus is associated with germ cell pluripotency. The exit of this complex from the nucleus correlates with germ cell differentiation, a process promoted by the up-regulation of Znrf3, a negative regulator of WNT/β-catenin signaling. Together, these data identify the molecular basis of the transition from primordial germ cells to oogonia and demonstrate that β-catenin is a central gatekeeper in ovarian differentiation and gametogenesis.//////////////////E-cadherin is a transmembrane glycoprotein responsible for physical connection of epithelial cells through
Ca(2+)-binding regions in its extracellular domain. E-cadherin-mediated cell-cell adhesion is effected by 3 cytoplasmic
proteins known as catenins alpha, beta, and gamma. These catenins are thought to work as connectors that anchor the
E-cadherin to the cytoskeletal actin bundle through the cadherin cytoplasmic domain. Dysfunction of this adhesion
complex causes dissociation of cancer cells from primary tumor nodules, thus possibly contributing to cancer invasion
and metastasis.
NCBI Summary: The protein encoded by this gene is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. The encoded protein also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. Finally, this protein binds to the product of the APC gene, which is mutated in adenomatous polyposis of the colon. Mutations in this gene are a cause of colorectal cancer (CRC), pilomatrixoma (PTR), medulloblastoma (MDB), and ovarian cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016] |
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| General function | Cell adhesion molecule, Cytoskeleton, Nucleic acid binding, DNA binding, Transcription factor | ||||
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| Cellular localization | Cytoplasmic, Nuclear | ||||
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| Ovarian function | Follicle development, Antral follicle growth, Ovulation, Steroid metabolism, Luteinization, Germ cell development, Oogenesis, Oocyte maturation | ||||
| Comment | Beta-catenin directs the transformation of testis Sertoli cells to ovarian granulosa-like cells by inducing Foxl2 expression. Li Y et al. (2017) Sertoli and granulosa cells are two major types of somatic cells in the male and female gonads,respectively. Previous studies have shown that Sertoli and granulosa cells are derived from common progenitor cells and that differentiation of these two cell types is regulated by sex differentiation genes. The signaling pathway including the adhesion and transcription factor Ctnnb1 (cadherin-associated protein, beta 1, also known as β-catenin) regulates differentiation of granulosa cells in the absence of the transcription factor Sry, and over-activation of β-catenin in the presence of Sry leads to granulosa prior to sex determination. Surprisingly, our previous study found that β-catenin over-activation in Sertoli cells after sex determination can also cause disruption of the testicular cord and aberrant testis development. However, the underlying molecular mechanism was unclear. In this study, we found that constitutive activation of Ctnnb1 in Sertoli cells led to ectopic expression of the granulosa cell-specific marker FOXL2 in testes. Co-staining experiments revealed that FOXL2-positive cells were derived from Sertoli cells, and Sertoli cells were transformed into granulosa-like cells after Ctnnb1 over-activation. Further studies demonstrated that CTNNB1 induced Foxl2 expression by directly binding to transcription factor Tcf/Lef binding sites in the FOXL2 promoter region. We also found that directly over-expression of Foxl2 indecreased the expression of Sertoli cell-specific genes in primary Sertoli cells. Taken together, these results demonstrate that repression of β-catenin (CTNNB1) signaling is required for lineage maintenance of Sertoli cells. Our study provides a new mechanism for Sertoli cell lineage maintenance during gonad development.////////////////// Protein kinase B is required for follicle-stimulating hormone mediated beta-catenin accumulation and estradiol production in granulosa cells of cattle. Gómez BI et al. (2015) Follicle-stimulating hormone regulation of ovarian estradiol (E2) production requires involvement of beta-catenin (CTNNB1), a transcriptional co-factor. In cultured granulosa cells (GC) of cattle, FSH treatment increased protein abundance of CTNNB1 as well as protein kinase B (AKT), a molecule known to regulate components of the CTNNB1 degradation complex. However, whether FSH induction of CTNNB1 is through direct modulation of AKT remains to be determined. To investigate specific contributions of AKT to CTNNB1 accumulation, GC were treated with insulin-like growth factor-I (IGF-I), a well-established AKT activator, in the presence or absence of FSH. Granulosa cells treated with FSH, IGF-I, and IGF-I plus FSH had increased CTNNB1 accumulation compared with controls (P≤0.02; n=6). E2 medium concentrations were greater (P=0.09; n=4) in FSH treated cells compared to controls (166 and 100±28pg/mL, respectively). Treatment with IGF-I and IGF-I plus FSH increased (P<0.01) E2 to comparable concentrations. Subsequently, GC treated with lithium chloride (LiCl), a pharmacological activator of AKT, provided a response consistent with IGF-I treated cells, as LiCl, FSH, and FSH plus LiCl increased CTNNB1 accumulation compared with non-treated controls (P≤0.03; n=3). In contrast, inhibition of AKT signaling with LY294002 suppressed the ability of FSH and IGF-I to regulate CTNNB1. Additionally, LY294002 treatment reduced FSH and IGF-I mediated E2 medium concentrations (P≤0.004). These results demonstrate that activation of AKT is required for gonadotropin regulation of CTNNB1 accumulation and subsequent ovarian E2 production.////////////////// Gonadal Identity in the Absence of Pro-Testis Factor SOX9 and Pro-Ovary Factor Beta-Catenin in Mice. Nicol B et al. (2015) Sex-reversal cases in humans and genetic models in mice have revealed that the fate of the bipotential gonad hinges upon the balance between pro-testis SOX9 and pro-ovary beta-catenin pathways. We wondered if SOX9 and beta-catenin define the gonads identity, what do the gonads become when both factors are absent? To answer this question, we developed mouse models that lack either Sox9, beta-catenin, or both in the somatic cells of the fetal gonads and examined the morphological outcomes and transcriptome profiles. In the absence of Sox9 and beta-catenin, both XX and XY gonads progressively lean toward the testis fate, indicating that expression of certain pro-testis genes requires the repression of the β-catenin pathway, rather than a direct activation by SOX9. We also observed that XY double knockout gonads were more masculinized than their XX counterpart. We aimed to identify the genes responsible for the initial events of gonad masculinization in SOX9/beta-catenin mutant embryos, and to determine how the genetic context (XX vs. XY) impacts this masculinization. Transcriptome comparisons showed that early molecular changes underlying the XY-specific masculinization involve the expression of Sry and 21 SRY direct target genes, such as Sox8 and Cyp26b1. These results imply that when both Sox9 and beta-catenin are absent, Sry is capable of activating other pro-testis genes and drive testis differentiation. Our findings not only provide insight into the mechanism of sex determination, but also identify candidate genes that are potentially involved in disorders of sex development.////////////////// Canonical WNT Signaling Inhibits Follicle Stimulating Hormone Mediated Steroidogenesis in Primary Cultures of Rat Granulosa Cells. Stapp AD 2014 et al. Beta-catenin (CTNNB1), a key component of wingless-type mouse mammary tumor virus integration site family (WNT) signaling, participates in follicle stimulated hormone-mediated regulation of estrogen (E2) production. The purpose of these studies was to determine if CTNNB1's contribution to FSH-mediated steroidogenesis in primary rat granulosa cells was due in part to extracellular stimulation of the canonical WNT signaling pathway. To achieve this purpose, primary cultures of rat granulosa cells were exposed to vehicle or a canonical member of the WNT signaling pathway, WNT3A, before co-culture and in the presence or absence of FSH for 24 h. Activation of the canonical WNT signaling pathway was determined by dose-dependent induction of Axin2 mRNA expression and stimulation of the CTNNB1/T cell factor promoter-reporter TOPflash. WNT pathway induction was demonstrated at doses of 50 and 500 ng/mL of WNT3A. Granulosa cells treated with WNT3A in combination with FSH had enhanced CTNNB1/T cell factor transcriptional activity above cells treated with WNT3A alone. Steroidogenic enzymes and ovarian differentiation factor mRNAs were quantified via quantitative PCR. Expression of steroidogenic enzyme mRNAs aromatase (Cyp19a1), P450 side chain cleavage (Cyp11a1), and steroidogenic acute regulatory protein (Star) were increased following FSH treatment. Co-incubation of WNT3A and FSH reduced the ability of FSH to stimulate steroidogenic enzymes and subsequent E2 and progesterone (P4) production. Concomitant activation of FSH and WNT pathways results in marked reduction of ovarian differentiation factors, LH receptor (Lhcgr) and inhibin-alpha (Inha). Therefore, WNT inhibits FSH target genes and steroid production associated with maturation and differentiation of the ovarian follicle. ///////////////////////// To beta or not to beta: Canonical beta-catenin signaling pathway and ovarian development. Tevosian SG et al. The mammalian embryonic gonad is a unique organ primordium in that it can adopt two different developmental fates-namely, differentiate as either a testis or an ovary-with dramatic consequences for an individual. While a molecular cascade culminating in testis development is well characterized, the ovarian pathways still remain enigmatic. The canonical Wnt/beta-catenin signaling implements a conserved mechanism of regulating gene expression that is integral to development of all metazoans. In this review, we summarize the recent evidence that suggests a central role for this signaling pathway in the development of the mammalian female. Developmental Dynamics, 2008. (c) 2008 Wiley-Liss, Inc. | ||||
| Expression regulated by | LH, Steroids | ||||
| Comment | Follicle-stimulating hormone regulation of estradiol production: possible involvement of WNT2 and ?catenin in bovine granulosa cells. Casta?BI et al. Follicle-stimulating hormone regulation of estrogen biosynthesis in the adult rodent ovary requires ?catenin (CTNNB1), but whether CTNNB1 is involved in FSH-induced estrogen production in cattle is unknown. To elucidate the effect of FSH in regulating specific wingless-type mouse mammary tumor virus integration site (WNT)/CTNNB1 pathway components in bovine folliculogenesis and steroidogenesis, granulosa cells and follicular fluid were collected from large antral follicles (8 to 22 mm) from ovaries containing stage-III corpora lutea (d 11 to 17 of an estrous cycle). Follicles were categorized as high estradiol (n = 3; = 25 ng/mL) or low estradiol (n = 3; = 14 ng/mL) based on intra-follicular estradiol concentrations. Protein fractions were collected from granulosa cells and CTNNB1 abundance was analyzed by Western blot. Follicles with high estradiol concentrations had 6-fold greater (P < 0.001) amounts of CTNNB1 compared to those classified as low-estradiol follicles, indicating that the hormonal milieu responsible for increased estradiol content could result in CTNNB1 accumulation. To ascertain specific contributions of FSH to increases in CTNNB1 protein levels, granulosa cells were isolated from small ovarian follicles (1 to 5 mm) and cultured in the presence or absence of 100 ng/mL FSH for 24 or 48 h. Real-time PCR quantification of aromatase (CYP19A1) and select WNT family members were evaluated in response to FSH treatment. Successful stimulation of granulosa cells with FSH was confirmed by induction of CYP19A1 mRNA and parallel temporal elevation of medium estradiol concentrations. Additionally, protein kinase b (AKT), a known FSH target increased 1.7-fold (P = 0.07). Of the WNT family members analyzed, only WNT2 mRNA was induced after 24 h of FSH treatment compared to controls (0.12-fold and 3.7-fold for control and FSH-treated, respectively; P < 0.05), and WNT2 expression tended (P = 0.11) to remain increased at 48 h in FSH-treated cells compared with controls (1.0- and 3.14-fold, respectively). Furthermore, FSH-treated granulosa cells had greater levels of total CTNNB1 (P = 0.04) protein. These data demonstrate for the first time that FSH regulates CTNNB1 protein and WNT2 mRNA expressions in bovine granulosa cells, suggesting a potential role of canonical WNT signaling in ovarian steroidogenesis and follicular growth of cattle. Future studies are necessary to determine if FSH directly regulates CTNNB1 through modulation of AKT or indirectly by up regulating WNT2, which subsequently activates the canonical WNT pathway. Follicle-stimulating hormone/cAMP regulation of aromatase gene expression requires {beta}-catenin. Parakh TN et al. Estrogens profoundly influence the physiology and pathology of reproductive and other tissues. Consequently, emphasis has been placed on delineating the mechanisms underlying regulation of estrogen levels. Circulating levels of estradiol in women are controlled by follicle-stimulating hormone (FSH), which regulates transcription of the aromatase gene (CYP19A1) in ovarian granulosa cells. Previous studies have focused on two downstream effectors of the FSH signal, cAMP and the orphan nuclear receptor steroidogenic factor-1 (NR5A1). In this report, we present evidence for beta-catenin (CTNNB1) as an essential transcriptional regulator of CYP19A1. FSH induction of select steroidogenic enzyme mRNAs, including Cyp19a1, is enhanced by beta-catenin. Additionally, beta-catenin is present in transcription complexes assembled on the endogenous gonad-specific CYP19A1 promoter, as evidenced by chromatin immunoprecipitation assays. Transient expression and RNAi studies demonstrate that FSH- and cAMP-dependent regulation of this promoter is sensitive to alterations in the level of beta-catenin. The stimulatory effect of beta-catenin is mediated through functional interactions with steroidogenic factor-1 that involve four acidic residues within its ligand-binding domain, mutation of which attenuates FSH/cAMP-induced Cyp19a1 mRNA accumulation. Together, these data demonstrate that beta-catenin is essential for FSH/cAMP-regulated gene expression in the ovary, identifying a central and previously unappreciated role for beta-catenin in estrogen biosynthesis, and a potential broader role in other aspects of follicular maturation. Luteinizing hormone regulates inhibin-a subunit expression through multiple signaling pathways involving steroidogenic factor-1 and beta-catenin in the macaque corpus luteum. Suresh PS et al. We employed different experimental model systems to define the role of GATA4, beta-catenin, and steroidogenic factor (SF-1) transcriptional factors in the regulation of monkey luteal inhibin secretion. Reverse transcription polymerase chain reactions and western blotting analyses show high expression of inhibin-a, GATA4, and beta-catenin in corpus luteum (CL) of the mid-luteal phase. Gonadotropin-releasing hormone receptor antagonist-induced luteolysis model suggested the significance of luteinizing hormone (LH) in regulating these transcriptional factors. Inducible cyclic AMP early repressor mRNA expression was detected in the CL and no change was observed in different stages of CL. Following amino acid sequence analysis, interaction between SF-1 and beta-catenin in mid-stage CL was verified by reciprocal co-immunoprecipitation experiments coupled to immunoblot analysis. Electrophoretic mobility shift analysis support the role of SF-1 in regulating luteal inhibin-a expression. Our results suggest a possible multiple crosstalk of Wnt, cAMP, and SF-1 in the regulation of luteal inhibin secretion. | ||||
| Ovarian localization | Oocyte, Cumulus, Granulosa, Theca, Luteal cells, Stromal cells, Surface epithelium, Ovarian tumor | ||||
| Comment | beta-catenin/Tcf-signaling appears to establish the murine ovarian surface epithelium (OSE) and remains active in selected postnatal OSE cells. Usongo M et al. ABSTRACT: BACKGROUND: Wnts are a family of secreted signaling molecules involved in a number of developmental processes including the establishment of cell fate, polarity and proliferation. Recent studies also implicate wnts in epithelial adult stem cell maintenance, renewal and differentiation. Wnts transduce their signal through one of three signaling pathways. The best studied, the wnt/beta-catenin pathway, leads to an increase in intracellular beta-catenin which acts as a cotranscription factor with members of the Tcf/Lef family. A number of wnts are expressed in the ovary, specifically in the membrana granulosa and ovarian surface epithelium (OSE). We investigated the spatio-temporal pattern of beta-catenin/Tcf expression in the OSE using responsive transgenic (TopGal) mice. RESULTS: The generated beta-galactosidase response (lacZ+) identified the cell population that overlies the medio-lateral surface of the indifferent gonad at embryonic day (E) 11.5. From E12.5 onwards, lacZ expression disappeared in cells covering the testis but remained with ovary development. LacZ+OSE cells were present throughout embryonic and postnatal ovarian development but demonstrated an age-dependent decrease to a small proportion when animals were weaned and remained at this proportion with aging. Flow cytometric (FACS) and ovarian section analyses showed lacZ+cells constitute approximately 20% of OSE in postnatal (day 1) mice which fell to 8% in 5 day-old animals while in prepubertal and adult mice this accounted for only 0.2% of OSE. Apoptosis was undetected in OSE of neonates and beta-catenin/Tcf-signaling cells were proliferative in neonatal mice indicating that neither cell death nor proliferation failure was responsible for the proportion alteration. It appeared that lacZ+cells give rise to lacZ-cells and this was confirmed in cell cultures. The DNA-binding dye DyeCycle Violet was used to set up the side population (SP) assay aimed at identifying subpopulations of OSE cells with chemoresistance phenotype associated with ABCG2 transporter activity. FACS analysis revealed lacZ+ cells exhibit cytoprotective mechanisms as indicated by enrichment within the SP. CONCLUSIONS: The study raises the possibility that wnt/beta-catenin-signaling cells constitute a progenitor cell population and could underlie the pronounced histopathology observed for human ovarian cancer. Davies BR, et al reported the epression of E-cadherin, alpha-catenin and beta-catenin in normal ovarian surface epithelium and epithelial ovarian cancers. Khan-Dawood FS, reported immunocytochemical localization and expression of E-cadherin and beta-catenin in the human corpus luteum. beta-catenin was observed in the cytoplasm of the luteal cells. Abundant expression of E-cadherin was observed by Western analysis in the early luteal phase and the level of expression was significantly different from that observed in the mid- and late luteal phase corpora lutea. In contrast the concentrations of beta-catenin were higher in the mid-luteal phase compared to the early luteal phase. | ||||
| Follicle stages | Primordial, Primary, Secondary, Antral | ||||
| Comment | ?catenin/Tcf-signaling in murine oocytes identifies non-ovulatory follicles. Usongo M et al. Wnts are secreted glycoproteins molecules that signal through one of three signaling pathways. The best characterized pathway involves stabilization of the multifunctional protein ?catenin which in concert with members of the T-cell factor (Tcf) family activates specific gene transcription. We have examined putative Wnt/?catenin in the murine ovary using transgenic mice harboring a reporter construct that activates ?galactosidase (lacZ) expression in response to ?catenin/Tcf binding (TopGal mice). Primordial and primary follicles did not stain for lacZ and the proportion of ?catenin/Tcf signaling oocytes was lower than that of non-signaling oocytes throughout estrous cycle. ?catenin/Tcf signaling oocytes were observed in follicles from the secondary stage of development and their proportion increased with follicular maturation (secondary follicles: 20%; early antral and antral 70%). In contrast, the majority (>90%) of ovulated oocytes did not stain for lacZ. Since the oocyte possesses components for Wnt signal transduction, our data suggest that ?catenin/Tcf-signaling is involved in the development of follicular ovulatory capability and identifies non-ovulatory follicles. | ||||
| Phenotypes | |||||
| Mutations |
7 mutations
Species: mouse
Species: mouse
Species: mouse
Species: mouse
Species: mouse
Species: human
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | May 3, 2000, midnight | by: |
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| last update: | July 28, 2021, 11:04 a.m. | by: | hsueh email: |
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