Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells

H Niwa, J Miyazaki, A G Smith

Research output: Contribution to journalArticlepeer-review

Abstract

Cell fate during development is defined by transcription factors that act as molecular switches to activate or repress specific gene expression programmes. The POU transcription factor Oct-3/4 (encoded by Pou5f1) is a candidate regulator in pluripotent and germline cells and is essential for the initial formation of a pluripotent founder cell population in the mammalian embryo. Here we use conditional expression and repression in embryonic stem (ES) cells to determine requirements for Oct-3/4 in the maintenance of developmental potency. Although transcriptional determination has usually been considered as a binary on-off control system, we found that the precise level of Oct-3/4 governs three distinct fates of ES cells. A less than twofold increase in expression causes differentiation into primitive endoderm and mesoderm. In contrast, repression of Oct-3/4 induces loss of pluripotency and dedifferentiation to trophectoderm. Thus a critical amount of Oct-3/4 is required to sustain stem-cell self-renewal, and up- or downregulation induce divergent developmental programmes. Our findings establish a role for Oct-3/4 as a master regulator of pluripotency that controls lineage commitment and illustrate the sophistication of critical transcriptional regulators and the consequent importance of quantitative analyses.
Original languageEnglish
Pages (from-to)372-6
Number of pages5
JournalNature Genetics
Volume24
Issue number4
DOIs
Publication statusPublished - Apr 2000

Keywords

  • Animals
  • Cell Differentiation
  • Cell Division
  • Cell Line
  • Cell Lineage
  • Clone Cells
  • DNA-Binding Proteins
  • Down-Regulation
  • Gene Expression Regulation, Developmental
  • Genes, Regulator
  • Genes, Reporter
  • Mice
  • Octamer Transcription Factor-3
  • RNA, Messenger
  • Stem Cells
  • Transcription Factors
  • Transcription, Genetic
  • Transfection
  • Up-Regulation

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