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Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and increases embryonic stem cell resistance to differentiation
Open accessAbstract
Self-renewal of rodent embryonic stem cells is enhanced by partial inhibition of glycogen synthase kinase-3 (Gsk3; refs , ). 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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Cites
The ground state of embryonic stem cell self-renewal
Ying, Q.-L., Wray, J., Nichols, J., Batlle-Morera, L., Doble, B., Woodgett, J., Cohen, P., & Smith, A. (2008) · Nature · doi:10.1038/nature06968 · Cited by 3,442
Self-citationFunctional interaction of β-catenin with the transcription factor LEF-1
Behrens, J., von Kries, J. P., Kühl, M., Bruhn, L., Wedlich, D., Grosschedl, R., & Birchmeier, W. (1996) · Nature · doi:10.1038/382638a0 · Cited by 2,912
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The many faces and functions of β‐catenin
Valenta, T., Hausmann, G., & Basler, K. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.150 · Cited by 1,598
A single-cell molecular map of mouse gastrulation and early organogenesis
Pijuan-Sala, B., Griffiths, J. A., Guibentif, C., Hiscock, T. W., Jawaid, W., Calero-Nieto, F. J., Mulas, C., Ibarra-Soria, X., Tyser, R. C. V., Ho, D. L. L., et al. (2019) · Nature · doi:10.1038/s41586-019-0933-9 · Cited by 1,033
YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response
Azzolin, L., Panciera, T., Soligo, S., Enzo, E., Bicciato, S., Dupont, S., Bresolin, S., Frasson, C., Basso, G., Guzzardo, V., et al. (2014) · Cell · doi:10.1016/j.cell.2014.06.013 · Cited by 1,094
Single Cell RNA-Sequencing of Pluripotent States Unlocks Modular Transcriptional Variation
Kolodziejczyk, A. A., Kim, J. K., Tsang, J. C. H., Ilicic, T., Henriksson, J., Natarajan, K. N., Tuck, A. C., Gao, X., Bühler, M., Liu, P., et al. (2015) · Cell Stem Cell · doi:10.1016/j.stem.2015.09.011 · Cited by 570
Dynamic stem cell states: Naive to primed pluripotency in rodents and humans
Weinberger, L., Ayyash, M., Novershtern, N., & Hanna, J. H. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2015.28 · Cited by 622
Metadata
- Authors
- Wray, J., Kalkan, T., Gomez-Lopez, S., Eckardt, D., Cook, A., Kemler, R., & Smith, A.
- Venue
- Nature Cell Biology
- Published
- 2011-06-19
- Volume
- 13
- Issue
- 7
- Pages
- 838-845
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2002511118
- Cited by
- 525
- References
- 2
- FWCI
- 20.22
- Type
- journal article
- Language
- en
- Open access
- green
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- Wray, J., Kalkan, T., Gomez-Lopez, S., Eckardt, D., Cook, A., Kemler, R., & Smith, A. (2011). Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and increases embryonic stem cell resistance to differentiation. Nature Cell Biology. https://doi.org/10.1038/ncb2267
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