Elevated p53 Activities Restrict Differentiation Potential of MicroRNA-Deficient Pluripotent Stem Cells

Zhong Liu, Cheng Zhang, Maria Skamagki, Alireza Khodadadi-Jamayran, Wei Zhang, Dexin Kong, Chia Wei Chang, Jingyang Feng, Xiaosi Han, Tim M. Townes, Hu Li, Kitai Kim, Rui Zhao

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1604-1617
Number of pages14
JournalStem Cell Reports
Volume9
Issue number5
DOIs
StatePublished - Nov 14 2017

Keywords

  • Dgcr8
  • apoptosis
  • differentiation
  • miR-302
  • microRNA
  • neural differentiation
  • nutlin-3a
  • p53
  • pluripotent stem cells

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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