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: 3.64). 01/2006; 288(1):276-83. DOI: 10.1016/j.ydbio.2005.09.045
Source: PubMed

ABSTRACT 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The uteri of adult conditional beta-catenin mutants are grossly deficient in smooth muscle of the myometrium, which has been replaced by adipose, a phenotype resembling human lipoleiomyoma.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. "
    Reproduction Fertility and Development 09/2014; DOI:10.1071/RD14079 · 2.58 Impact Factor
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    • "MSC can differentiate into a variety of tissues, including muscle, bone, cartilage, and fat. Wnt signaling, one of the key factors controlling MSC fate, inhibits adipogenesis and enhances myogenesis or osteoblastogenesis (Arango et al. 2005; Bodine et al. 2004). "
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    ABSTRACT: Adipogenesis, a key step in the pathogenesis of obesity, involves extensive ECM remodeling, changes in cell-ECM interactions, and cytoskeletal rearrangement. Matricellular proteins regulate cell-cell and cell-ECM interactions. Evidence in vivo and in vitro indicates that the prototypic matricellular protein, SPARC, inhibits adipogenesis and promotes osteoblastogenesis. Herein we discuss mechanisms underlying the inhibitory effect of SPARC on adipogenesis. SPARC enhances the Wnt/β-catenin signaling pathway and regulates the expression and posttranslational modification of collagen. SPARC might drive preadipocytes away from the status of growth arrest and therefore prevent terminal differentiation. SPARC could also decrease WAT deposition through its negative effects on angiogenesis. Therefore, several stages of white adipose tissue accumulation are sensitive to the inhibitory effects of SPARC.
    Journal of Cell Communication and Signaling 12/2009; 3(3):247-254. DOI:10.1007/s12079-009-0064-4
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    • "Therefore, Dicer may be important for the generation of miRNAs that regulate smooth muscle differentiation or maintenance. Interestingly, Müllerian duct mesenchymespecific knockout of beta-catenin results in smaller uteri and a deficiency of myometrium that is replaced by adipose tissue (Arango et al. 2005). These findings are consistent with the idea that miRNAs may be important for maintaining correct Wnt signaling for myometrial differentiation. "
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    ABSTRACT: Dicer encodes a riboendonuclease required for microRNA biosynthesis. Dicer was inactivated in Müllerian duct mesenchyme-derived tissues of the reproductive tract of the mouse, using an Amhr2-Cre allele. Although Amhr2-Cre; Dicer conditional mutant males appeared normal and were fertile, mutant females were infertile. In adult mutant females, there was a reduction in the size of the oviducts and uterine horns. The oviducts were less coiled compared to controls and cysts formed at the isthmus near the uterotubal junction. Unfertilized, degenerate oocytes were commonly found within these cysts, indicating a defect in embryo transit. Beads transferred into the mutant oviduct failed to migrate into the uterus. In addition, blastocysts transferred directly into the mutant uterus did not result in pregnancy. Histological analysis demonstrated that the mutant uterus contained less glandular tissue and often the few glands that remained were found within the myometrium, an abnormal condition known as adenomyosis. In adult mutants, there was ectopic expression of Wnt4 and Wnt5a in the luminal epithelium (LE) and glandular epithelium (GE) of the uterus, and Wnt11 was ectopically expressed in GE. These results demonstrate that Dicer is necessary for postnatal differentiation of Müllerian duct mesenchyme-derived tissues of the female reproductive tract, suggesting that microRNAs are important regulators of female reproductive tract development and fertility.
    Molecular Reproduction and Development 07/2009; 76(7):678-88. DOI:10.1002/mrd.21010 · 2.68 Impact Factor
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