Elevated p53 activities restrict differentiation potential of microRNA-deficient pluripotent stem cells Journal Article
| Authors: | Liu, Z.; Zhang, C.; Skamagki, M.; Khodadadi-Jamayran, A.; Zhang, W.; Kong, D.; Chang, C. W.; Feng, J.; Han, X.; Townes, T. M.; Li, H.; Kim, K.; Zhao, R. |
| Article Title: | Elevated p53 activities restrict differentiation potential of microRNA-deficient pluripotent stem cells |
| Abstract: | Pluripotent stem cells (PSCs) deficient for microRNAs (miRNAs), such as Dgcr8−/− or Dicer−/– embryonic stem cells (ESCs), contain no mature miRNA and cannot differentiate into somatic cells. How miRNA deficiency causes differentiation defects remains poorly understood. Here, we report that miR-302 is sufficient to enable neural differentiation of differentiation-incompetent Dgcr8−/− ESCs. Our data showed that miR-302 directly suppresses the tumor suppressor p53, which is modestly upregulated in Dgcr8−/− ESCs and serves as a barrier restricting neural differentiation. We demonstrated that direct inactivation of p53 by SV40 large T antigen, a short hairpin RNA against Trp53, or genetic ablation of Trp53 in Dgcr8−/− PSCs enables neural differentiation, while activation of p53 by the MDM2 inhibitor nutlin-3a in wild-type ESCs inhibits neural differentiation. Together, we demonstrate that a major function of miRNAs in neural differentiation is suppression of p53 and that modest activation of p53 blocks neural differentiation of miRNA-deficient PSCs. In this article, Zhao and colleagues show that expression of miR-302 is sufficient to enable neural differentiation of differentiation-incompetent Dgcr8−/− ESCs. The authors demonstrated that miR-302 directly suppresses p53, which serves as a barrier restricting neural differentiation. © 2017 The Authors |
| Keywords: | immunohistochemistry; controlled study; unclassified drug; nonhuman; biological marker; animal cell; mouse; somatic cell; apoptosis; microrna; gene expression profiling; embryonic stem cell; animal experiment; animal model; nutlin 3; protein p53; immunoblotting; virus large t antigen; simian virus 40; down regulation; upregulation; pluripotent stem cells; nerve cell differentiation; short hairpin rna; p53; differentiation; microtubule associated protein 2; mir-302; nutlin-3a; neural differentiation; induced pluripotent stem cell; priority journal; article; dgcr8; tuj1 protein |
| Journal Title: | Stem Cell Reports |
| Volume: | 9 |
| Issue: | 5 |
| ISSN: | 2213-6711 |
| Publisher: | Cell Press |
| Date Published: | 2017-11-14 |
| Start Page: | 1604 |
| End Page: | 1617 |
| Language: | English |
| DOI: | 10.1016/j.stemcr.2017.10.006 |
| PROVIDER: | scopus |
| PMCID: | PMC5688240 |
| PUBMED: | 29141234 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 January 2018 -- Source: Scopus |
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