Abstract

The pluripotency of embryonic stem (ES) cells is thought to be maintained by a few key transcription factors, including Oct3/4 and Sox2. The function of Oct3/4 in ES cells has been extensively characterized, but that of Sox2 has yet to be determined. Sox2 can act synergistically with Oct3/4 in vitro to activate Oct–Sox enhancers, which regulate the expression of pluripotent stem cell-specific genes, including Nanog, Oct3/4 and Sox2 itself. These findings suggest that Sox2 is required by ES cells for its Oct–Sox enhancer activity. Using inducible Sox2-null mouse ES cells, we show that Sox2 is dispensable for the activation of these Oct–Sox enhancers. In contrast, we demonstrate that Sox2 is necessary for regulating multiple transcription factors that affect Oct3/4 expression and that the forced expression of Oct3/4 rescues the pluripotency of Sox2-null ES cells. These results indicate that the essential function of Sox2 is to stabilize ES cells in a pluripotent state by maintaining the requisite level of Oct3/4 expression.

1. Laboratory for Pluripotent Cell Studies, RIKEN Center for Developmental Biology, Minatojima-minamimachi 2-2-3, Chu-o-ku, Kobe, Hyogo 650-0047, Japan.
2. CREST (Core Research for Evolutional Science and Technology), Japan Science and Technology Agency, Honcho 4-1-8, Kawaguchi, Saitama 332-0012, Japan.
3. Division of Molecular Biology and Cell Engineering, Department of Regenerative Medicine, Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
4. Laboratory for Development and Regenerative Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunokicho, Chu-o-ku, Kobe, Hyogo 650-0017, Japan.
5. Department of Regenerative Medicine, Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
6. Division of Developmental Biology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1241, Japan.
7. Developmental Genomics and Aging Section, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, 333 Cassell Drive, Suite 3000, Baltimore, MD 21224-6820, USA.

Correspondence to: Shinji Masui^1,2,3 e-mail: masui@ri.imcj.go.jp

Correspondence to: Hitoshi Niwa^1,2,4 e-mail: niwa@cdb.riken.jp

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