title: Inflammation and disruption of the mucosal architecture in claudin-7-deficient mice.
abstract: OBJECTIVE
  Integrity of the intestinal epithelium is required for nutrition absorption and defense against pathogens. Claudins are cell adhesion molecules that localize at tight junctions (TJs); many are expressed in the intestinal tract, but little is known about their functions. Claudin-7 is unique in that it has a stronger basolateral membrane distribution than other claudins, which localize primarily to apical TJs in the intestinal epithelium. We investigated the basolateral functions of claudin-7 and assessed the effects of disruption of Cldn7 in intestines of mice.
  
  
  METHODS
  We generated Cldn7(-/-) mice and examined their intestines by histology, molecular and cellular biology, and biochemistry approaches. We performed gene silencing experiments in epithelial cell lines using small interfering RNAs (siRNAs).
  
  
  RESULTS
  The Cldn7(-/-) mice had severe intestinal defects that included mucosal ulcerations, epithelial cell sloughing, and inflammation. Intestines of Cldn7(-/-) mice produced significantly higher levels of cytokines, the nuclear factor κB p65 subunit, and cyclooxygenase 2; they also up-regulated expression of matrix metalloproteinases (MMPs)-3 and -7. siRNA in epithelial cell lines showed that the increased expression of MMP-3 resulted directly from claudin-7 depletion, whereas that of MMP-7 resulted from inflammation. Electron microscopy analysis showed that intestines of Cldn7(-/-) mice had intercellular gaps below TJs and cell matrix loosening. Deletion of Cldn7 reduced expression and altered localization of the integrin α2 subunit in addition to disrupting formation of complexes of claudin-7, integrin α2, and claudin-1 that normally form in epithelial basolateral compartments of intestines.
  
  
  CONCLUSIONS
  In mice, claudin-7 has non-TJ functions, including maintenance of epithelial cell-matrix interactions and intestinal homeostasis.
authors: Department of Anatomy and Cell Biology, East Carolina University Brody School of Medicine, Greenville, North Carolina 27834, USA.
authors: Lei
authors: L
authors: Ding
authors: Zhe
authors: Z
authors: Lu
authors: Oded
authors: O
authors: Foreman
authors: Rodney
authors: R
authors: Tatum
authors: Qun
authors: Q
authors: Lu
authors: Randall
authors: R
authors: Renegar
authors: Jian
authors: J
authors: Cao
authors: Yan-Hua
authors: YH
authors: Chen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D062445:Claudin-1; D057167:Claudins / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D039421:Integrin alpha2 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000648:ultrastructure; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019108:Tight Junctions / Q000378:metabolism* / Q000648:ultrastructure; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D062445:Claudin-1; D057167:Claudins; C568113:Cldn1 protein, mouse; C507360:Cldn7 protein, mouse; D039421:Integrin alpha2; D008565:Membrane Proteins; D051996:Transcription Factor RelA; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse; D020783:Matrix Metalloproteinase 7