Inhibition of Glycogen Synthase Kinase-3 Alleviates Tcf3 Repression of the Pluripotency Network and Increases Embryonic Stem Cell Resistance to Differentiation

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2011 Jun 21

PMID 21685889

Citations 297

Authors

Jason Wray

Tuzer Kalkan

Sandra Gomez-Lopez

Dominik Eckardt

Andrew Cook

Rolf Kemler

Austin Smith

Affiliations

Soon will be listed here.

Abstract

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-catenin, stabilization of Myc protein and global de-inhibition of anabolic processes. 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 domain. 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 genes 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.

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