Stabilization of beta-catenin in the mouse zygote leads to premature epithelial-mesenchymal transition in the epiblast.
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.
Kemler
Rolf
R
Max-Planck Institute of Immunobiology, Stuebeweg 51, 79108 Freiburg, Germany. kemler@immunbio.mpg.de
Hierholzer
Andreas
A
Kanzler
Benoît
B
Kuppig
Stefan
S
Hansen
Kati
K
Taketo
Makoto M
MM
de Vries
Wilhelmine N
WN
Knowles
Barbara B
BB
Solter
Davor
D
D000483:Alleles; D000818:Animals; D001755:Blastocyst / Q000378:metabolism*; D019521:Body Patterning; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000737:chemistry* / Q000378:metabolism; D004475:Ectoderm / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism*; D005091:Exons; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007763:Lac Operon; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000737:chemistry* / Q000378:metabolism; D019076:Transgenes; D025801:Ubiquitin / Q000378:metabolism; D015053:Zygote / Q000378:metabolism*; D051176:beta Catenin; D001616:beta-Galactosidase / Q000378:metabolism
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D025801:Ubiquitin; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D001616:beta-Galactosidase; D046988:Proteasome Endopeptidase Complex