Hepatocyte-specific deletion of Cdc42 results in delayed liver regeneration after partial hepatectomy in mice

Authors

  • Haixin Yuan,

    1. State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    2. Graduate School of the Chinese Academy of Sciences, Shanghai, China
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    • These authors contributed equally to this study.

  • Hong Zhang,

    1. State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    2. Graduate School of the Chinese Academy of Sciences, Shanghai, China
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    • These authors contributed equally to this study.

  • Xunwei Wu,

    1. Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
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  • Zhe Zhang,

    1. State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
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  • Dan Du,

    1. State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    2. Graduate School of the Chinese Academy of Sciences, Shanghai, China
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  • Wenchao Zhou,

    1. State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    2. Graduate School of the Chinese Academy of Sciences, Shanghai, China
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  • Shuhua Zhou,

    1. State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    2. Graduate School of the Chinese Academy of Sciences, Shanghai, China
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  • Cord Brakebusch,

    1. Biomedical Institute, BRIC, University of Copenhagen, Copenhagen, Denmark
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  • Zhengjun Chen

    Corresponding author
    1. State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    • Shanghai Institute of Biochemistry and Cell Biology, 320 Yueyang Road, Shanghai 200031, China
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    • Fax: (86)-21-54921071.


  • Potential conflict of interest: Nothing to report.

Abstract

Cdc42, a member of the Rho guanosine triphosphatase (GTPase) family, plays important roles in the regulation of the cytoskeleton, cell proliferation, cell polarity, and cellular transport, but little is known about its specific function in mammalian liver. We investigated the function of Cdc42 in regulating liver regeneration. Using a mouse model with liver-specific knockout of Cdc42 (Cdc42LK), we studied liver regeneration after partial hepatectomy. Histological analysis, immunostaining, and western blot analysis were performed to characterize Cdc42LK livers and to explore the role of Cdc42 in liver regeneration. In control mouse livers, Cdc42 became activated between 3 and 24 hours after partial hepatectomy. Loss of Cdc42 led to a significant delay of liver recovery after partial hepatectomy, which was associated with reduced and delayed DNA synthesis indicated by 5-bromo-2′-deoxyuridine staining. Consistent with this, expression of cyclins D1, A, and E was markedly delayed or reduced in Cdc42LK livers during regeneration. As a potential effector of Cdc42, Rac1 activation was dramatically attenuated in Cdc42LK livers after partial hepatectomy, suggesting it is regulated in a Cdc42-dependent manner. Activation of certain proliferative signaling pathways, such as extracellular signal–regulated kinase, c-Jun N-terminal kinase, and p70S6 kinase pathways, was delayed in Cdc42LK livers. In addition, dilated bile canaliculi and excessive lipid accumulation were observed in mutant livers during liver regeneration, which may result from impaired cytoskeletal organization and intracellular trafficking in hepatocytes. Conclusion: Our results revealed important roles of Cdc42 in the regulation of proliferative signaling during liver regeneration. (HEPATOLOGY 2009:49:240-249.)

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