Constitutive Activation of Beta-Catenin in Uterine Stroma and Smooth Muscle Leads to the Development of Mesenchymal Tumors in Mice1

Tanwar, Pradeep S.; Lee, Ho‐Joon; Zhang, Li Hua; Zukerberg, Lawrence; Taketo, Makoto Mark; Rueda, Bo R.; Teixeira, Jose

doi:10.1095/biolreprod.108.075648

Cited by 134 publications

(140 citation statements)

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“…Focal retention of the MD could occur if expression and accumulation of CA β-catenin is delayed until after E13.5 because removing MIS-producing testes from the organ culture assay after only 1 d of incubation still results in MD regression (33). Delayed expression of Amhr2-Cre could also explain the discrepancy between the previously reported requirement for nuclear β-catenin during MD regression (15) and normal differentiation of reproductive tract tissues in female mice with CA β-catenin expression in the MD mesenchyme (17). This leads us to speculate whether induced expression of CA β-catenin earlier than that which we achieved by Cre expression in the Amhr2 locus might result in greater MD retention.…”

Section: Discussionmentioning

confidence: 93%

“…We have previously reported that expression of CA β-catenin restricted to the uterine stroma and myometrium leads to myometrial smooth muscle cell hyperplasia and development of mesenchymal tumors in murine uteri (17). We and others have also shown that CA β-catenin causes sterility in males by inhibiting postnatal Sertoli maturation and spermatogenesis (18)(19)(20).…”

mentioning

confidence: 89%

“…Nuclear β-catenin expression in the MD mesenchyme has been suggested as a mediator of MIS-induced MD regression (15). We have previously shown that expression of a tissue-specific, constitutively activated (CA) form of β-catenin (16) driven by Cre in the Amhr2 locus (AMHR2-Cre) did not result in MD regression in female mice (17), suggesting that β-catenin is not sufficient for regression.…”

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confidence: 99%

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Focal Müllerian duct retention in male mice with constitutively activated β-catenin expression in the Müllerian duct mesenchyme

Tanwar¹,

Zhang²,

Tanaka³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Müllerian-inhibiting substance (MIS), which is produced by fetal Sertoli cells shortly after commitment of the bipotential gonads to testicular differentiation, causes Müllerian duct (MD) regression. In the fetal female gonads, MIS is not expressed and the MDs will differentiate into the internal female reproductive tract. We have investigated whether dysregulated β-catenin activity affects MD regression by expressing a constitutively activated nuclear form of β-catenin in the MD mesenchyme. We show that constitutively activated (CA) β-catenin causes focal retention of MD tissue in the epididymides and vasa deferentia. In adult mutant mice, the retained MD tissues express α-smooth muscle actin and desmin, which are markers for uterine differentiation. MD retention inhibited the folding complexity of the developing epididymides and usually led to obstructive azoospermia by spermatoceles. The MDs of urogenital ridges from mutant female embryos showed less regression with added MIS in organ culture compared with control MDs when analyzed by whole mount in situ hybridization for Wnt7a as a marker for the MD epithelium. CA β-catenin did not appear to affect expression of either MIS in the embryonic testes or its type II receptor (AMHR2) in the MD mesenchyme nor did it inhibit pSmad1/5/8 nuclear accumulation, suggesting that dysregulated β-catenin must inhibit MD regression independently of MIS signaling. These studies suggest that dysregulated Wnt/β-catenin signaling in the MD mesenchyme might also be a contributing factor in persistent Müllerian duct syndrome, a form of male pseudohermaphroditism, and development of spermatoceles.anti-Müllerian hormone | epididymis | Mullerian inhibiting substance type II receptor (MISRII or MISR2) | spermatocele | epididymis

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Section: Discussionmentioning

confidence: 93%

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confidence: 89%

mentioning

confidence: 99%

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Focal Müllerian duct retention in male mice with constitutively activated β-catenin expression in the Müllerian duct mesenchyme

Tanwar¹,

Zhang²,

Tanaka³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…We have targeted NR2F2 and CTNNB1 in this study based on their significant potential for a causal role in uterine fibroid pathophysiology , Tanwar et al 2009). We report that NR2F2 and CTNNB1 levels are altered in human uterine fibroids and that both proteins display strong blood vessel localisation in myometrial and fibroid tissues.…”

Section: Discussionmentioning

confidence: 99%

“…In uterine biology, CTNNB1 plays roles in menstruation (Nei et al 1999) and implantation (Mohamed et al 2005, Jeong et al 2009) and has been linked to endometrial hyperplasia and cancer (Fukuchi et al 1998, Nei et al 1999, Jeong & McMahon 2005. Suggestive of a causative role in uterine fibroid development is the observation that sustained Ctnnb1 expression in transgenic mice results in uterine mesenchymal tumours, which are histologically similar to human uterine leiomyoma (Tanwar et al 2009). NR2F2 belongs to the steroid/thyroid hormone receptor superfamily and plays important roles in development, including cell differentiation, cell cycle and migration, and angiogenesis (see review Boudot et al (2011)).…”

Section: Introductionmentioning

confidence: 99%

Aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids

Zaitseva¹,

Holdsworth-Carson²,

Waldrip³

et al. 2013

Reproduction

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Uterine fibroids are the most common benign tumour afflicting women of reproductive age. Despite the large healthcare burden caused by fibroids, there is only limited understanding of the molecular mechanisms that drive fibroid pathophysiology. Although a large number of genes are differentially expressed in fibroids compared with myometrium, it is likely that most of these differences are a consequence of the fibroid presence and are not causal. The aim of this study was to investigate the expression and regulation of NR2F2 and CTNNB1 based on their potential causal role in uterine fibroid pathophysiology. We used real-time quantitative RT-PCR, western blotting and immunohistochemistry to describe the expression of NR2F2 and CTNNB1 in matched human uterine fibroid and myometrial tissues. Primary myometrial and fibroid smooth muscle cell cultures were treated with progesterone and/or retinoic acid (RA) and sonic hedgehog (SHH) conditioned media to investigate regulatory pathways for these proteins. We showed that NR2F2 and CTNNB1 are aberrantly expressed in fibroid tissue compared with matched myometrium, with strong blood vessel-specific localisation. Although the SHH pathway was shown to be active in myometrial and fibroid primary cultures, it did not regulate NR2F2 or CTNNB1 mRNA expression. However, progesterone and RA combined regulated NR2F2 mRNA, but not CTNNB1, in myometrial but not fibroid primary cultures.In conclusion, we demonstrate aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids compared with normal myometrium, consistent with the hypothesis that these factors may play a causal role uterine fibroid development.

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