Sall4 Is Essential for Stabilization, But Not for Pluripotency, of Embryonic Stem Cells by Repressing Aberrant Trophectoderm Gene Expression

Authors

  • Shunsuke Yuri,

    1. Division of Integrative Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
    2. Global COE “Cell Fate Regulation Research and Education Unit” Kumamoto University, Kumamoto, Japan
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  • Sayoko Fujimura,

    1. Division of Integrative Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
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  • Keisuke Nimura,

    1. Department of Molecular Therapeutics, Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Osaka, Japan
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  • Naoki Takeda,

    1. Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan
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  • Yayoi Toyooka,

    1. Laboratory of Pluripotent Cell Studies, RIKEN Center for Developmental Biology, Kobe, Japan
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  • Yu-Ichi Fujimura,

    1. RIKEN Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Japan
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  • Hiroyuki Aburatani,

    1. Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
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  • Kiyoe Ura,

    1. Department of Molecular Therapeutics, Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Osaka, Japan
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  • Haruhiko Koseki,

    1. RIKEN Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Japan
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  • Hitoshi Niwa,

    1. Laboratory of Pluripotent Cell Studies, RIKEN Center for Developmental Biology, Kobe, Japan
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  • Ryuichi Nishinakamura

    Corresponding author
    1. Division of Integrative Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
    2. Global COE “Cell Fate Regulation Research and Education Unit” Kumamoto University, Kumamoto, Japan
    • Division of Integrative Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan
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    • Telephone: +81-96-373-6615; Fax: +81-96-373-6618


  • First published online in STEM CELLSExpress January 22, 2009.

  • Author contributions: S.Y.: collection and assembly of data, data analysis and interpretation, manuscript writing; S.F.: collection and assembly of data; K.N.: collection and assembly of data; N.T.: collection and assembly of data; Y.T.: collection and assembly of data; Y.-I.F.: collection and assembly of data; H.A.: collection and assembly of data; K.U.: data analysis and interpretation; H.K.: data analysis and interpretation; H.N.: Provision of study material, data analysis and interpretation; R.N.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing.

Abstract

Sall4 is a mouse homolog of a causative gene of the autosomal dominant disorder Okihiro syndrome. We previously showed that the absence of Sall4 leads to lethality during peri-implantation and that Sall4-null embryonic stem (ES) cells proliferate poorly with intact pluripotency when cultured on feeder cells. Here, we report that, in the absence of feeder cells, Sall4-null ES cells express the trophectoderm marker Cdx2, but are maintained for a long period in an undifferentiated state with minimally affected Oct3/4 expression. Feeder-free Sall4-null ES cells contribute solely to the inner cell mass and epiblast in vivo, indicating that these cells still retain pluripotency and do not fully commit to the trophectoderm. These phenotypes could arise from derepression of the Cdx2 promoter, which is normally suppressed by Sall4 and the Mi2/NuRD HDAC complex. However, proliferation was impaired and G1 phase prolonged in the absence of Sall4, suggesting another role for Sall4 in cell cycle control. Although Sall1, also a Sall family gene, is known to genetically interact with Sall4 in vivo, Sall1-null ES cells have no apparent defects and no exacerbation is observed in ES cells lacking both Sall1 and Sall4, compared with Sall4-null cells. This suggests a unique role for Sall4 in ES cells. Thus, though Sall4 does not contribute to the central machinery of the pluripotency, it stabilizes ES cells by repressing aberrant trophectoderm gene expression. STEM CELLS 2009;27:796–805

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