Inhibition of β-catenin–TCF1 interaction delays differentiation of mouse embryonic stem cells
| Autor: | Tenzin Gocha, Matthew Murphy, Foster C. Gonsalves, Penelope Hayward, Steven S. Shen, Abil Saj, Xiaoqian Zhang, Ramanuj DasGupta, Aviv Madar, Betul Akgol Oksuz, Sujash S. Chatterjee, Alfonso Martinez Arias |
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| Rok vydání: | 2015 |
| Předmět: |
Homeobox protein NANOG
Beta-catenin Transcription Genetic Cellular differentiation Rex1 Immunology Mice 03 medical and health sciences 0302 clinical medicine SOX2 Report Animals Immunology and Allergy Hepatocyte Nuclear Factor 1-alpha Cell Self Renewal Oxazoles Research Articles Cells Cultured beta Catenin 030304 developmental biology 0303 health sciences biology Wnt signaling pathway Cell Differentiation Mouse Embryonic Stem Cells Cell Biology Embryonic stem cell Cell biology 3. Good health biology.protein Stem cell 030217 neurology & neurosurgery |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | Blocking β-catenin/TCF1–mediated transcriptional activation with a specific small molecule or by TCF1 knockdown delays the mouse embryonic stem cell differentiation program and enhances pluripotency. 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/β-catenin pathway promotes pluripotency by alleviating T cell factor TCF3-mediated repression of the PTN. However, it has remained unclear how β-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 β-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 β-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. |
| Databáze: | OpenAIRE |
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