title: Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells.
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.
authors.affiliation: Centre for Genome Research, The University of Edinburgh, King's Buildings, Edinburgh, UK.
authors.forename: H
authors.initials: H
authors.lastname: Niwa
authors.forename: J
authors.initials: J
authors.lastname: Miyazaki
authors.forename: A G
authors.initials: AG
authors.lastname: Smith
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D019070:Cell Lineage; D002999:Clone Cells / Q000166:cytology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D005809:Genes, Regulator; D017930:Genes, Reporter; D051379:Mice; D050814:Octamer Transcription Factor-3; D012333:RNA, Messenger / Q000096:biosynthesis; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors