Conditional deletion of β-catenin in the mesenchyme of the developing mouse uterus results in a switch to adipogenesis in the myometrium

Pediatric Surgical Research Laboratories/CPZN6202, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge St., Boston, MA 02114, USA.
Developmental Biology (Impact Factor: 3.55). 01/2006; 288(1):276-83. DOI: 10.1016/j.ydbio.2005.09.045
Source: PubMed


Precise cell fate decisions during differentiation of uterine tissues from the embryonic Müllerian duct are critical for normal fertility. Wnt-7a, a member of the Wnt family of secreted signaling molecules that can signal through a canonical beta-catenin pathway, is necessary for the correct differentiation of both anterior/posterior and radial axes of the uterus. In order to investigate the role of beta-catenin directly in mouse uterine development, we have generated mice that are deficient in beta-catenin expression in the embryonic Müllerian duct. We have found that conditional deletion of beta-catenin in the Müllerian duct mesenchyme before postnatal differentiation of the uterine layers results in a phenotype that is distinct from the phenotype observed by deletion of Wnt-7a. Shortly after birth, the uteri of the conditional mutants appear smaller and less organized. The uteri of adult conditional beta-catenin mutants are grossly deficient in smooth muscle of the myometrium, which has been replaced by adipose, a phenotype resembling human lipoleiomyoma. We also show that the adipocytes in the uteri of mice conditionally deleted for beta-catenin are derived from Müllerian inhibiting substance type II receptor-expressing cells suggesting that they share a common origin with the uterine smooth muscle cells. These results describe the first molecular evidence linking disruption of beta-catenin expression in mesenchymal cells with a switch from myogenesis to adipogenesis in vivo.

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    • "Wnt9b acts upstream of Wnt4 in this process (Carroll et al. 2005). Conditional deletion of b-catenin in the Müllerian duct mesenchyme results in abnormal uteri after birth and a lack of uterine smooth muscle, underscoring the importance of canonical Wnt signalling for the development of Müllerian duct derivatives (Arango et al. 2005). In contrast, Tanwar et al. (2009) showed that conditional activation of b-catenin by Amhr2–Cre results in the formation of large tumorous growths and multiple haemorrhagic sites on the surface of the uterus in mice. "
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    ABSTRACT: The integration of a complex network of signalling molecules promotes implantation of the blastocyst and development of the placenta. These processes are crucial for a successful pregnancy and fetal growth and development. The signalling network involves both cell-cell and cell-extracellular matrix communication. The family of secreted glycoprotein ligands, the Wnts, plays a major role in regulating a wide range of biological processes, including embryonic development, cell fate, proliferation, migration, stem cell maintenance, tumour suppression, oncogenesis and tissue homeostasis. Recent studies have provided evidence that Wnt signalling pathways play an important role in reproductive tissues and in early pregnancy events. The focus of this review is to summarise our present knowledge of expression, regulation and function of the Wnt signalling pathways in early pregnancy events of human and other model systems, and its association with pathological conditions. Despite our recent progress, much remains to be learned about Wnt signalling in human reproduction. The advancement of knowledge in this area has applications in the reduction of infertility and the incidence and morbidity of gestational diseases.
    Reproduction Fertility and Development 09/2014; DOI:10.1071/RD14079 · 2.40 Impact Factor
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    • "Taken together, these studies support a dual role for WNT/β-catenin signaling in MD biology, one for regression in males and another for differentiation in females. We have shown that either conditional knockout of β-catenin or constitutive activation of β-catenin in the MD mesenchyme leads to myometrial pathologies in female mice (Arango et al., 2005; Tanwar et al., 2009) and that constitutive activation of β-catenin in the MD mesenchyme predisposes male mice to focal MD retention (Tanwar et al., 2010). Thus, it appears that the contradictory finding that MD retention in males with either β-catenin knockout (Kobayashi et al., 2011) or constitutive activation of β-catenin (Tanwar et al., 2010) using the same Misr2-driven Cre would suggest that MD regression is exquisitely sensitive to WNT/ β-catenin signaling in the MD mesenchyme or that highly localized microenvironmental factors that modulate WNT/β-catenin signaling might need to act in concert with β-catenin to complete MD regression in males. "
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    ABSTRACT: A key event during mammalian sexual development is regression of the Müllerian ducts (MDs) in the bipotential urogenital ridges (UGRs) of fetal males, which is caused by the expression of Müllerian inhibiting substance (MIS) in the Sertoli cells of the differentiating testes. The paracrine signaling mechanisms involved in MD regression are not completely understood, particularly since the receptor for MIS, MISR2, is expressed in the mesenchyme surrounding the MD, but regression occurs in both the epithelium and mesenchyme. Microarray analysis comparing MIS signaling competent and Misr2 knockout embryonic UGRs was performed to identify secreted factors that might be important for MIS-mediated regression of the MD. A seven-fold increase in the expression of Wif1, an inhibitor of WNT/β-catenin signaling, was observed in the Misr2-expressing UGRs. Whole mount in situ hybridization of Wif1 revealed a spatial and temporal pattern of expression consistent with Misr2 during the window of MD regression in the mesenchyme surrounding the MD epithelium that was absent in both female UGRs and UGRs knocked out for Misr2. Knockdown of Wif1 expression in male UGRs by Wif1-specific siRNAs beginning on embryonic day 13.5 resulted in MD retention in an organ culture assay, and exposure of female UGRs to added recombinant human MIS induced Wif1 expression in the MD mesenchyme. Knockdown of Wif1 led to increased expression of β-catenin and its downstream targets TCF1/LEF1 in the MD mesenchyme and to decreased apoptosis, resulting in partial to complete retention of the MD. These results strongly suggest that WIF1 secretion by the MD mesenchyme plays a role in MD regression in fetal males.
    Developmental Biology 12/2013; 386(1). DOI:10.1016/j.ydbio.2013.12.015 · 3.55 Impact Factor
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    • "Given the fact that Wnt signaling is important for organ development and tissue homeostasis, it may not be surprising that the pathway also has major roles in uterus formation, growth and differentiation. Gene targeting in mice revealed that β -catenin and different Wnts, such as Wnt4, Wnt5a, or Wnt7a, are critical for uterine development (Miller and Sassoon, 1998; Vainio et al., 1999; Mericskay et al., 2004; Arango et al., 2005). Wnt signaling components also play a role in stroma cell proliferation and differentiation for example Wnt4, Wnt6 (Li et al., 2013; Wang et al., 2013) or Dkk1, a progesterone-regulated gene which is induced in the endometrium upon decidualization (Tulac et al., 2006; Duncan et al., 2011). "
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    ABSTRACT: Wingless ligands, a family of secreted proteins, are critically involved in organ development and tissue homeostasis by ensuring balanced rates of stem cell proliferation, cell death and differentiation. Wnt signaling components also play crucial roles in murine placental development controlling trophoblast lineage determination, chorioallantoic fusion and placental branching morphogenesis. However, the role of the pathway in human placentation, trophoblast development and differentiation is only partly understood. Here, we summarize our present knowledge about Wnt signaling in the human placenta and discuss its potential role in physiological and aberrant trophoblast invasion, gestational diseases and choriocarcinoma formation. Differentiation of proliferative first trimester cytotrophoblasts into invasive extravillous trophoblasts is associated with nuclear recruitment of β -catenin and induction of Wnt-dependent T-cell factor 4 suggesting that canonical Wnt signaling could be important for the formation and function of extravillous trophoblasts. Indeed, activation of the pathway was shown to promote trophoblast invasion in different in vitro trophoblast model systems as well as trophoblast cell fusion. Methylation-mediated silencing of inhibitors of Wnt signaling provided evidence for epigenetic activation of the pathway in placental tissues and choriocarcinoma cells. Similarly, abundant nuclear expression of β -catenin in invasive trophoblasts of complete hydatidiform moles suggested a role for hyper-activated Wnt signaling. In contrast, upregulation of Wnt inhibitors was noticed in placentae of women with preeclampsia, a disease characterized by shallow trophoblast invasion and incomplete spiral artery remodeling. Moreover, changes in Wnt signaling have been observed upon cytomegalovirus infection and in recurrent abortions. In summary, the current literature suggests a critical role of Wnt signaling in physiological and abnormal trophoblast function.
    Frontiers in Genetics 09/2013; 4:190. DOI:10.3389/fgene.2013.00190
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