title: Differential requirements for β-catenin during mouse development.
abstract: Embryogenesis relies on the precise interplay of signaling cascades to activate tissue-specific differentiation programs. An important player in these morphogenetic processes is β-catenin, which is a central component of adherens junctions and canonical Wnt signaling. Lack of β-catenin is lethal before gastrulation, but mice heterozygous for β-catenin (Ctnnb1) develop as wild type. Here, we confine β-catenin amounts below the heterozygous expression level to study the functional consequences for development. We generate embryonic stem (ES) cells and embryos expressing β-catenin only from the ubiquitously active ROSA26 promoter and thereby limit β-catenin expression to ~12.5% (ROSA26(β/+)) or ~25% (ROSA26(β/β)) of wild-type levels. ROSA26(β/+) is sufficient to maintain ES cell morphology and pluripotent characteristics, but is insufficient to activate canonical target genes upon Wnt stimulation. This Wnt signaling deficiency is incompletely restored in ROSA26(β/β) ES cells. We conclude that even very low β-catenin levels are able to sustain cell adhesion, but not Wnt signaling. During development, ROSA26(β/β) as well as ROSA26(β/+) partially rescues the knockout phenotype, yet proper gastrulation is absent. These embryos differentiate according to the neural default hypothesis, indicating that gastrulation depends on high β-catenin levels. Strikingly, if ROSA26(β/+) or ROSA26(β/β) is first activated after gastrulation, subsequent development correlates with the dosage of β-catenin. Moreover, molecular evidence indicates that the amount of β-catenin controls the induction of specific Wnt target genes. In conclusion, by restricting its expression we determine the level of β-catenin required for adhesion or pluripotency and during different morphogenetic events.
authors.affiliation: Max-Planck Institute of Immunobiology and Epigenetics, Department of Molecular Embryology, 79108 Freiburg, Germany. rudloff@ie-freiburg.mpg.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Rudloff
authors.forename: Rolf
authors.initials: R
authors.lastname: Kemler
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D047108:Embryonic Development / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D054262:Gastrulation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D022661:RNA, Untranslated; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D011506:Proteins; D022661:RNA, Untranslated; D051153:Wnt Proteins; D051176:beta Catenin