|Title||Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells.|
|Publication Type||Journal Article|
|Year of Publication||2000|
|Authors||Niwa H, Miyazaki J, Smith AG|
|Date Published||2000 Apr|
|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|
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.
|Alternate Journal||Nat. Genet.|