期刊
NATURE CELL BIOLOGY
卷 13, 期 7, 页码 762-U383出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb2283
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资金
- American Cancer Society [RSG GGC 112994]
- National Institutes of Health [R01-CA128571, R01-GM065400]
- Howard Hughes Medical Institute
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 beta-catenin-binding effectors of Wnt signalling suggested Tcf3-beta-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-beta-catenin and Tcf1-beta-catenin interactions contributed to Wnt stimulation of self-renewal and gene expression, and the combination of Tcf3 and Tcf1 recruited Wnt-stabilized beta-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.
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