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Molecular and Cellular Biology, March 2002, p. 1526-1536, Vol. 22, No. 5
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.5.1526-1536.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Phenotypic Complementation Establishes Requirements for Specific POU Domain and Generic Transactivation Function of Oct-3/4 in Embryonic Stem Cells

Hitoshi Niwa,1,2,3* Shinji Masui,3 Ian Chambers,2 Austin G. Smith,2 and Jun-ichi Miyazaki1

Stem Cell Regulation Research, Area of Molecular Therapeutics, Course of Advanced Medicine, Osaka University Graduate School of Medicine, Suita C, Osaka 565-0871,1 Laboratory for Pluripotent Cell Studies, RIKEN Center for Developmental Biology, Chu-o-ku, Kobe 650-0047, Japan,3 Centre for Genome Research, University of Edinburgh, Edinburgh EH9 3JQ, United Kingdom2

Received 2 July 2001/ Returned for modification 18 September 2001/ Accepted 28 November 2001

Transcription factors of the POU family govern cell fate through combinatorial interactions with coactivators and corepressors. The POU factor Oct-3/4 can define differentiation, dedifferentation, or self-renewal of pluripotent embryonic stem (ES) cells in a sensitive, dose-dependent manner (H. Niwa, J.-I. Miyazali, and A. G. Smith, Nat. Genet. 24:372-376, 2000). Here we have developed a complementation assay based on the ability of Oct-3/4 transgenes to rescue self-renewal in conditionally null ES cells and used this to define which domains of Oct-3/4 are required to sustain the undifferentiated stem cell phenotype. Surprisingly, we found that molecules lacking either the N-terminal or C-terminal transactivation domain, though not both, can effectively replace full-length Oct-3/4. Furthermore, a fusion of the heterologous transactivation domain of Oct-2 to the Oct-3/4 POU domain can also sustain self-renewal. Thus, the unique function of Oct-3/4 in ES cell propagation resides in combination of the specific POU domain with a generic proline-rich transactivation domain. Interestingly, however, Oct-3/4 target gene expression elicited by the N- and C-terminal transactivation domains is not identical, indicating that at least one class of genes activated by Oct-3/4 is not required for ES cell propagation.

* Corresponding author. Mailing address: Laboratory for Pluripotent Cell Studies, RIKEN Center for Developmental Biology, Minatojima-Minamimachi 2-2-3, Chu-o-ku, Kobe 650-0047, Japan. Phone: 81-78-306-0156. Fax: 81-78-306-0101. E-mail: niwa{at}rtc.riken.go.jp.

Molecular and Cellular Biology, March 2002, p. 1526-1536, Vol. 22, No. 5
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.5.1526-1536.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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