Claudins and JAM-A coordinately regulate tight junction formation and epithelial polarity

  • Tetsuhisa Otani
    Division of Cell Structure, National Institute for Physiological Sciences, Okazaki, Aichi, Japan 1
  • Thanh Phuong Nguyen
    Division of Cell Structure, National Institute for Physiological Sciences, Okazaki, Aichi, Japan 1
  • Shinsaku Tokuda
    Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 3
  • Kei Sugihara
    Department of Anatomy and Cell Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan 4
  • Taichi Sugawara
    Division of Cell Structure, National Institute for Physiological Sciences, Okazaki, Aichi, Japan 1
  • Kyoko Furuse
    Division of Cell Structure, National Institute for Physiological Sciences, Okazaki, Aichi, Japan 1
  • Takashi Miura
    Department of Anatomy and Cell Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan 4
  • Klaus Ebnet
    Institute-Associated Research Group “Cell Adhesion and Cell Polarity,” Institute of Medical Biochemistry, Zentrum für Molekularbiologie der Entzündung, University of Münster, Münster, Germany 5
  • Mikio Furuse
    Division of Cell Structure, National Institute for Physiological Sciences, Okazaki, Aichi, Japan 1

Description

<jats:p>Tight junctions (TJs) establish the epithelial barrier and are thought to form a membrane fence to regulate epithelial polarity, although the roles of TJs in epithelial polarity remain controversial. Claudins constitute TJ strands in conjunction with the cytoplasmic scaffolds ZO-1 and ZO-2 and play pivotal roles in epithelial barrier formation. However, how claudins and other TJ membrane proteins cooperate to organize TJs remains unclear. Here, we systematically knocked out TJ components by genome editing and show that while ZO-1/ZO-2–deficient cells lacked TJ structures and epithelial barriers, claudin-deficient cells lacked TJ strands and an electrolyte permeability barrier but formed membrane appositions and a macromolecule permeability barrier. Moreover, epithelial polarity was disorganized in ZO-1/ZO-2–deficient cells, but not in claudin-deficient cells. Simultaneous deletion of claudins and a TJ membrane protein JAM-A resulted in a loss of membrane appositions and a macromolecule permeability barrier and in sporadic epithelial polarity defects. These results demonstrate that claudins and JAM-A coordinately regulate TJ formation and epithelial polarity.</jats:p>

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