Journal
DEVELOPMENT
Volume 139, Issue 20, Pages 3711-3721Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.085597
Keywords
beta-catenin gene dosage; Pluripotency; Gastrulation; Mouse morphogenesis
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Funding
- Max-Planck Society
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Embryogenesis relies on the precise interplay of signaling cascades to activate tissue-specific differentiation programs. An important player in these morphogenetic processes is beta-catenin, which is a central component of adherens junctions and canonical Wnt signaling. Lack of beta-catenin is lethal before gastrulation, but mice heterozygous for beta-catenin (Ctnnb1) develop as wild type. Here, we confine beta-catenin amounts below the heterozygous expression level to study the functional consequences for development. We generate embryonic stem (ES) cells and embryos expressing beta-catenin only from the ubiquitously active ROSA26 promoter and thereby limit beta-catenin expression to similar to 12.5% (ROSA26(beta/+)) or similar to 25% (ROSA26(beta/beta)) of wild-type levels. ROSA26(beta/+) 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(beta/beta) ES cells. We conclude that even very low.-catenin levels are able to sustain cell adhesion, but not Wnt signaling. During development, ROSA26(beta/beta) as well as ROSA26(beta/+) 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 beta-catenin levels. Strikingly, if ROSA26(beta/+) or ROSA26(beta/beta) is first activated after gastrulation, subsequent development correlates with the dosage of beta-catenin. Moreover, molecular evidence indicates that the amount of beta-catenin controls the induction of specific Wnt target genes. In conclusion, by restricting its expression we determine the level of beta-catenin required for adhesion or pluripotency and during different morphogenetic events.
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