Abstract
The ability of mouse embryonic stem cells (mESCs) to self-renew or differentiate into various cell lineages is regulated by signaling pathways and a core pluripotency transcriptional network (PTN) comprising Nanog, Oct4, and Sox2. The Wnt/ß-catenin pathway promotes pluripotency by alleviating T cell factor TCF3-mediated repression of the PTN. However, it has remained unclear how ß-catenin's function as a transcriptional activator with TCF1 influences mESC fate. Here, we show that TCF1-mediated transcription is up-regulated in differentiating mESCs and that chemical inhibition of ß-catenin/TCF1 interaction improves long-term self-renewal and enhances functional pluripotency. Genetic loss of TCF1 inhibited differentiation by delaying exit from pluripotency and conferred a transcriptional profile strikingly reminiscent of self-renewing mESCs with high Nanog expression. Together, our data suggest that ß-catenin's function in regulating mESCs is highly context specific and that its interaction with TCF1 promotes differentiation, further highlighting the need for understanding how its individual protein-protein interactions drive stem cell fate.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 39-51 |
| Number of pages | 13 |
| Journal | Journal of Cell Biology |
| Volume | 211 |
| Issue number | 1 |
| DOIs | |
| State | Published - Oct 12 2015 |
Bibliographical note
Funding Information:This work was supported by the the National Institutes of Health (grant 1R01CA155125-01 to R. DasGupta and NCI-1T32CA160002 to M. Murphy), GIS Institutional Funds (GIS/14-ARB3207), NYSTEM (Shared Facilities for Stem Cell Research grant N09S-012, postdoctoral training fellowship C026880 to S.S. Chatterjee, and C026880 to M. Murphy), NYU RNAi Core (screening subsidy grant to R. DasGupta), Wellcome Trust (to A.M. Arias and P. Hayward), the National Center for Advancing Translational Sciences (grant UL1 TR00038), and National Institutes of Health (to NYU OCS Cores and Shared Resources).
Funding Information:
We thank A. Smith, B. Merrill, I. Aifantis, C. Basilico, L. Dailey, A. Mansukhani, B. Doble, E. Hernando, and I. Lemishka for cell lines and reagents; and U. Basu-Roy, S. Buckley, P. Cowin, M. Schober, J. Brown, M. Murtha, and members of the RD Laboratory and New York University (NYU) Langone Medical Center Cancer Institute and Stem Cell Program for helpful comments and discussions. We also thank members of the NYU research support groups, especially RNAi Core (Director C. Yun), Cytometry and Cell Sorting Core (Director P. Lopez), Genome Technology Center (Director A. Heguy), and High Performance Computing Facility (Associate Technology Director E. Peskin) for significant help with experimental setup and data processing. Finally, we thank the Institute for Cellular and Molecular Biology Histopathology core (A*Star; Senior Veterinary Pathologist M. Al-Haddawi) for histopathological evaluation of teratoma samples. This work was supported by the the National Institutes of Health (grant 1R01CA155125-01 to R. DasGupta and NCI-1T32CA160002 to M. Murphy), GIS Institutional Funds (GIS/14-ARB3207), NYS TEM (Shared Facilities for Stem Cell Research grant N09S-012, postdoctoral training fellowship C026880 to S.S. Chatterjee, and C026880 to M. Murphy), NYU RNAi Core (screening subsidy grant to R. DasGupta), Wellcome Trust (to A.M. Arias and P. Hayward), the National Center for Advancing Translational Sciences (grant UL1 TR00038), and National Institutes of Health (to NYU OCS Cores and Shared Resources).