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Molecular and Cellular Biology, April 2003, p. 2699-2708, Vol. 23, No. 8
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.8.2699-2708.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Fbx15 Is a Novel Target of Oct3/4 but Is Dispensable for Embryonic Stem Cell Self-Renewal and Mouse Development

Yoshimi Tokuzawa,1 Eiko Kaiho,1 Masayoshi Maruyama,1 Kazutoshi Takahashi,1 Kaoru Mitsui,1 Mitsuyo Maeda,2 Hitoshi Niwa,3 and Shinya Yamanaka1*

Laboratory of Animal Molecular Technology, Research and Education Center for Genetic Information, Nara Institute of Science and Technology, Ikoma, Nara 630-0192,1 First Department of Anatomy, Osaka City University Medical School, Osaka 545-8585,2 Laboratory of Pluripotent Cell Studies, RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan3

Received 8 August 2002/ Returned for modification 1 November 2002/ Accepted 19 December 2002

Embryonic stem (ES) cells are immortal and pluripotent cells derived from early mammalian embryos. Transcription factor Oct3/4 is essential for self-renewal of ES cells and early mouse development. However, only a few Oct3/4 target genes have been identified. In this study, we found that F-box-containing protein Fbx15 was expressed predominantly in mouse undifferentiated ES cells. Inactivation of Oct3/4 in ES cells led to rapid extinction of Fbx15 expression. Reporter gene analyses demonstrated that this ES cell-specific expression required an 18-bp enhancer element located approximately 500 nucleotides upstream from the transcription initiation site. The enhancer contained an octamer-like motif and an adjacent Sox-binding motif. Deletion or point mutation of either motif abolished the enhancer activity. The 18-bp fragment became active in NIH 3T3 cells when Oct3/4 and Sox2 were coexpressed. A gel mobility shift assay demonstrated cooperative binding of Oct3/4 and Sox2 to the enhancer sequence. In mice having a ß-galactosidase gene knocked into the Fbx15 locus, 5-bromo-4-chloro-3-indolyl-ß-D-galactopyranoside staining was detected in ES cells, early embryos (two-cell to blastocyst stages), and testis tissue. Despite such specific expression of Fbx15, homozygous mutant mice showed no gross developmental defects and were fertile. Fbx15-null ES cells were normal in morphology, proliferation, and differentiation. These data demonstrate that Fbx15 is a novel target of Oct3/4 but is dispensable for ES cell self-renewal, development, and fertility.

* Corresponding author. Mailing address: Laboratory of Animal Molecular Technology, Research and Education Center for Genetic Information, Nara Institute of Science and Technology, Ikoma, Nara 630-0101, Japan. Phone: 81-743-72-5591. Fax: 81-743-72-5599. E-mail: shinyay{at}gtc.aist-nara.ac.jp.

Molecular and Cellular Biology, April 2003, p. 2699-2708, Vol. 23, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.8.2699-2708.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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