Wnt/?-catenin signaling promotes differentiation, not self-renewal, of human embryonic stem cells and is repressed by Oct4.

ABSTRACT: Signal transduction pathways play diverse, context-dependent roles in vertebrate development. In studies of human embryonic stem cells (hESCs), conflicting reports claim Wnt/?-catenin signaling promotes either self-renewal or differentiation. We use a sensitive reporter to establish that Wnt/?-catenin signaling is not active during hESC self-renewal. Inhibiting this pathway over multiple passages has no detrimental effect on hESC maintenance, whereas activating signaling results in loss of self-renewal and induction of mesoderm lineage genes. Following exposure to pathway agonists, hESCs exhibit a delay in activation of ?-catenin signaling, which led us to postulate that Wnt/?-catenin signaling is actively repressed during self-renewal. In support of this hypothesis, we demonstrate that OCT4 represses ?-catenin signaling during self-renewal and that targeted knockdown of OCT4 activates ?-catenin signaling in hESCs. Using a fluorescent reporter of ?-catenin signaling in live hESCs, we observe that the reporter is activated in a very heterogeneous manner in response to stimulation with Wnt ligand. Sorting cells on the basis of their fluorescence reveals that hESCs with elevated ?-catenin signaling express higher levels of differentiation markers. Together these data support a dominant role for Wnt/?-catenin signaling in the differentiation rather than self-renewal of hESCs.

SUBMITTER: Davidson KC 

PROVIDER: S-EPMC3311359 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature