Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal
Author: ["Fei Yi","Laura Pereira","Jackson A. Hoffman","Brian R. Shy","Courtney M. Yuen","David R. Liu","Bradley J. Merrill"]
Publication: Nature Cell Biology
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Abstract
The co-occupancy of Tcf3 with Oct4, Sox2 and Nanog on embryonic stem cell (ESC) chromatin indicated that Tcf3 has been suggested to play an integral role in a poorly understood mechanism underlying Wnt-dependent stimulation of mouse ESC self-renewal of mouse ESCs. Although the conventional view of Tcf proteins as the β-catenin-binding effectors of Wnt signalling suggested Tcf3–β-catenin activation of target genes would stimulate self-renewal, here we show that an antagonistic relationship between Wnt3a and Tcf3 on gene expression regulates ESC self-renewal. Genetic ablation of Tcf3 replaced the requirement for exogenous Wnt3a or GSK3 inhibition for ESC self-renewal, demonstrating that inhibition of Tcf3 repressor is the necessary downstream effect of Wnt signalling. Interestingly, both Tcf3–β-catenin and Tcf1–β-catenin interactions contributed to Wnt stimulation of self-renewal and gene expression, and the combination of Tcf3 and Tcf1 recruited Wnt-stabilized β-catenin to Oct4 binding sites on ESC chromatin. This work elucidates the molecular link between the effects of Wnt and the regulation of the Oct4/Sox2/Nanog network. Inhibition of the repressor function of the Wnt3a effector β-catenin–TCF3 is shown to be required to maintain pluripotency in cooperation with the activating role of the second Wnt effector β-catenin–TCF1. Both Tcf3 and Tcf1 are involved in the recruitment of β-catenin to Oct4 binding sites in embryonic stem cell chromatin.
Cite this article
Yi, F., Pereira, L., Hoffman, J. et al. Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal. Nat Cell Biol 13, 762–770 (2011). https://doi.org/10.1038/ncb2283
