Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and

Abstract

The self-renewal of mouse embryonic stem cells is enhanced by inhibiting glycogen synthase kinase-3 (Gsk3). β-catenin is now found to be necessary for this effect through its interaction with Tcf3 to abrogate its repressive action for the expression of genes from the core pluripotency network. Self-renewal of rodent embryonic stem cells is enhanced by partial inhibition of glycogen synthase kinase-3 (Gsk3; refs 1, 2). This effect has variously been attributed to stimulation of Wnt signalling by β-catenin1, stabilization of Myc protein3 and global de-inhibition of anabolic processes4. Here we demonstrate that β-catenin is not necessary for embryonic stem cell identity or expansion, but its absence eliminates the self-renewal response to Gsk3 inhibition. Responsiveness is fully restored by truncated β-catenin lacking the carboxy-terminal transactivation domain5. However, requirement for Gsk3 inhibition is dictated by expression of T-cell factor 3 (Tcf3) and mediated by direct interaction with β-catenin. Tcf3 localizes to many pluripotency genes6 in embryonic stem cells. Our findings confirm that Tcf3 acts as a transcriptional repressor and reveal that β-catenin directly abrogates Tcf3 function. We conclude that Gsk3 inhibition stabilizes the embryonic stem cell state primarily by reducing repressive influence on the core pluripotency network.

Cite this article

Wray, J., Kalkan, T., Gomez-Lopez, S. et al. Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and increases embryonic stem cell resistance to differentiation. Nat Cell Biol 13, 838–845 (2011). https://doi.org/10.1038/ncb2267

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