Stabilization of beta-catenin in the mouse zygote leads to premature epithelial-mesenchymal transition in the epiblast.

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Animals, Blastocyst, Body-Patterning, Cell-Differentiation, Cell-Nucleus, Cytoskeletal-Proteins, Ectoderm, Epithelium, Exons, Genes-Reporter, Glycogen-Synthase-Kinase-3, Immunohistochemistry, In-Situ-Hybridization, Lac-Operon, Mesoderm, Mice, Mice-Inbred-C57BL, Mutation, Oocytes, Phenotype, Proteasome-Endopeptidase-Complex, Signal-Transduction, Time-Factors, Trans-Activators, Transgenes, Ubiquitin, Zygote

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Development 2004 Dec; 131(23):5817-24.


Many components of the Wnt/beta-catenin signaling pathway are expressed during mouse pre-implantation embryo development, suggesting that this pathway may control cell proliferation and differentiation at this time. We find no evidence for a functional activity of this pathway in cleavage-stage embryos using the Wnt-reporter line, BAT-gal. To further probe the activity of this pathway, we activated beta-catenin signaling by mating a zona pellucida3-cre (Zp3-cre) transgenic mouse line with a mouse line containing an exon3-floxed beta-catenin allele. The result is expression of a stabilized form of beta-catenin, resistant to degradation by the GSK3beta-mediated proteasome pathway, expressed in the developing oocyte and in each cell of the resulting embryos. Nuclear localization and signaling function of beta-catenin were not observed in cleavage-stage embryos derived from these oocytes. These results indicate that in pre-implantation embryos, molecular mechanisms independent of the GSK3beta-mediated ubiquitination and proteasome degradation pathway inhibit the nuclear function of beta-catenin. Although the mutant blastocysts initially developed normally, they then exhibited a specific phenotype in the embryonic ectoderm layer of early post-implantation embryos. We show a nuclear function of beta-catenin in the mutant epiblast that leads to activation of Wnt/beta-catenin target genes. As a consequence, cells of the embryonic ectoderm change their fate, resulting in a premature epithelial-mesenchymal transition.

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