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 cells1,
2,
3,
4 and is
essential for the initial formation of a pluripotent founder cell population
in the mammalian embryo5. 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.
