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

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The uteri of adult conditional beta-catenin mutants are grossly deficient in smooth muscle of the myometrium, which has been replaced by adipose, a phenotype resembling human lipoleiomyoma.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.

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

“…Cultures were carried out in the presence or absence of recombinant human MIS (44). At the end of the experiments, the urogenital ridges were fixed overnight in 4% paraformaldehyde at 4°C and used to perform whole mount in situ hybridization as described elsewhere (29,45). Briefly, Amhr2 (46) and Wnt7a (10) riboprobes were prepared using a MaxiScript kit from Ambion with digoxigenin and detected with antidigoxigenin F(ab) 2 fragments and BM purple (all from Roche).…”

Loss of APC function in mesenchymal cells surrounding the Müllerian duct leads to myometrial defects in adult mice

“…Myometrial defects were also observed by others by employing comparable models to either induce or inhibit Wnt/β-catenin signalling in utero. Arango et al (2005) used the Amhr2Cre model to induce β-catenin depletion and observed profound myometrial defects (Arango et al, 2005). In that study, β-catenin depletion in mesenchymal cells surrounding the Müllerian ducts resulted in the appearance of adipocytes replacing myometrial cells.…”

Update of Wnt signaling in implantation and decidualization

“…Besides Wnt7a, Wnt5a loss also disrupted the differentiation of Müllerian duct. In contrast to Wnt7a, targeted gene deletion of Wnt5a generated death at birth and induced defects in posterior growth of the FRT [66]. The Wnt5a mutant FRT still remained the anterior Müllerian-derived structures (normal oviducts but short and convoluted uterine horns), whereas lost the more posterior-derived structures (cervix and vagina).…”

“…The expression patterns of Wnt5a within the stroma and Wnt7a within the LE, and the similar phenotypes of the Wnt5a and Wnt7a mutants in glandular formation suggested that these Wnt ligands may interact to control uterine gland development. Wnt5a was thought to promote LE to change fate, invaginate, and form glands via downregulating Wnt7a [66].…”