Retinoic acid signaling positively regulates liver specification by inducing wnt2bb gene expression in medaka

Authors

  • Takahiro Negishi,

    1. Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
    2. Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
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  • Yoko Nagai,

    1. Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
    2. Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
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  • Yoichi Asaoka,

    1. Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
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  • Mami Ohno,

    1. Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
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  • Misako Namae,

    1. Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
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  • Hiroshi Mitani,

    1. Department of Integrated Biosciences, Graduate School of Frontier Science, University of Tokyo, Chiba, Japan
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  • Takashi Sasaki,

    1. Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan
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  • Nobuyoshi Shimizu,

    1. Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan
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  • Shuji Terai,

    1. Department of Gastroenterology & Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
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  • Isao Sakaida,

    1. Department of Gastroenterology & Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
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  • Hisato Kondoh,

    1. Japan Science and Technology Agency, Solution Oriented Research for Science and Technology Kondoh Research Team, Kyoto, Japan
    2. Department of Frontier Biosciences, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
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  • Toshiaki Katada,

    1. Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
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  • Makoto Furutani-Seiki,

    1. Japan Science and Technology Agency, Solution Oriented Research for Science and Technology Kondoh Research Team, Kyoto, Japan
    2. Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Bath, UK
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  • Hiroshi Nishina

    Corresponding author
    1. Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
    • Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
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    • fax: (81)-3-5803-5829.


  • Potential conflict of interest: Nothing to report.

Abstract

During vertebrate embryogenesis, the liver develops at a precise location along the endodermal primitive gut tube because of signaling delivered by adjacent mesodermal tissues. Although several signaling molecules have been associated with liver formation, the molecular mechanism that regulates liver specification is still unclear. We previously performed a screen in medaka to isolate mutants with impaired liver development. The medaka hio mutants exhibit a profound (but transient) defect in liver specification that resembles the liver formation defect found in zebrafish prometheus (prt) mutants, whose mutation occurs in the wnt2bb gene. In addition to their liver abnormality, hio mutants lack pectoral fins and die after hatching. Positional cloning indicated that the hio mutation affects the raldh2 gene encoding retinaldehyde dehydrogenase type2 (RALDH2), the enzyme principally responsible for retinoic acid (RA) biosynthesis. Mutations of raldh2 in zebrafish preclude the development of pectoral fins. Interestingly, in hio mutants, expression of wnt2bb in the lateral plate mesoderm (LPM) directly adjacent to the liver-forming endoderm was completely lost. Conclusion: Our data reveal the unexpected finding that RA signaling positively regulates the wnt2bb gene expression required for liver specification in medaka. These results suggest that a common molecular mechanism may underlie liver and pectoral fin specification during piscine embryogenesis. (HEPATOLOGY 2009.)

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