Cdc42 is crucial for the establishment of epithelial polarity during early mammalian development

Authors

  • Xunwei Wu,

    1. University of Copenhagen, Institute of Molecular Pathology, Copenhagen, Denmark
    Current affiliation:
    1. Cutaneous Biology Research Center (CBRC) Massachusetts General Hospital, Harvard Medical School, Charlestown, MA02129
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    • Drs. Wu and Li contributed equally to this work.

  • Shaohua Li,

    1. Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Piscataway, New Jersey
    Current affiliation:
    1. Department of Surgery, Robert Wood Johnson Medical School, New Brunswick, NJ 08903
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    • Drs. Wu and Li contributed equally to this work.

  • Anna Chrostek-Grashoff,

    1. Max Planck Institute of Biochemistry, Department of Molecular Medicine, Martinsried, Germany
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  • Aleksandra Czuchra,

    1. Max Planck Institute of Biochemistry, Department of Molecular Medicine, Martinsried, Germany
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  • Hannelore Meyer,

    1. Max Planck Institute of Biochemistry, Department of Molecular Medicine, Martinsried, Germany
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  • Peter D. Yurchenco,

    1. Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Piscataway, New Jersey
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  • Cord Brakebusch

    Corresponding author
    1. University of Copenhagen, Institute of Molecular Pathology, Copenhagen, Denmark
    • University of Copenhagen, BRIC, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark
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Abstract

To study the role of Cdc42 in the establishment of epithelial polarity during mammalian development, we generated murine Cdc42-null embryonic stem cells and analyzed peri-implantation development using embryoid bodies (EBs). Mutant EBs developed endoderm and underlying basement membrane, but exhibited defects of cell polarity, cell–cell junctions, survival, and cavitation. These defects corresponded to a decreased phosphorylation and membrane localization of aPKC, a reduced phosphorylation of GSK3β, and a diminished activity of Rac1. However, neither Rac1 nor the kinase function of GSK3β seem to contribute to cell polarization and cell–cell contacts. In contrast, EBs expressing dominant-negative (dn) PKCζ mimicked well the phenotype of Cdc42-null EBs, suggesting a major role of aPKC in mediating cell polarization downstream of Cdc42. Finally, aggregation experiments with endodermal cell lines suggested that Cdc42 might affect formation of adherens and tight junctions by PKCζ-dependent regulation of the protein levels of p120 catenin and E-cadherin. Developmental Dynamics 236:2767–2778, 2007. © 2007 Wiley-Liss, Inc.

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