β-catenin perturbations control differentiation programs in mouse embryonic stem cells

The Wnt/β-catenin pathway is involved in development, cancer and embryonic stem cell (ESC) maintenance; its dual role in stem cell self-renewal and differentiation is still controversial. Here, we applied an elegant in vitro system enabling conditional β-catenin control in β-catenin null mouse ESCs. We report that moderate activation of the canonical Wnt pathway via β-catenin genetic manipulation enhances epiblast stem cell (EpiSC) derivation in vitro. Using a different genetic model and β-catenin chemical modulation, we derive a new protocol for ESCs to EpiSCs differentiation, based on NDfi227 and the GSK3α/β inhibitor Chiron, that is more efficient than standard FGF2/ActivinA-based protocols. Finally, we report that moderate β-catenin favours early stem cell commitment towards mesoderm if overexpressed in the ground state of pluripotency only, or endoderm if the overexpression is maintained also during the differentiation, unravelling the controversial role of this signalling pathway at the exit from pluripotency.