Quantitative Expression of Oct-3/4 Defines Differentiation, Dedifferentiation or Self-Renewal of ES Cells

Nat Genet. 2000 Apr;24(4):372-6. doi: 10.1038/74199.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • DNA-Binding Proteins
  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • RNA, Messenger
  • Transcription Factors