title: Megaintestine in claudin-15-deficient mice.
abstract: OBJECTIVE
  Claudins, the major components of tight junction (TJ) strands, which form paracellular barriers, consist of 24 family members, the combination of which determines the properties of TJ-based paracellular barriers. Here, we generated claudin-15-deficient (Cldn15(-/-)) mice to examine the ubiquitously expressed functions of claudin-15.
  
  
  METHODS
  We generated Cldn15(-/-) mice by the conventional gene-targeting strategy. Because the upper small intestine was enlarged in Cldn15(-/-) mice, we analyzed the phenotype from various angles regarding histology, physiology, and cell biology.
  
  
  RESULTS
  Cldn15(-/-) mice were born and grew normally with an enlarged upper small intestinal phenotype, megaintestine. Deficiency of claudin-15 did not cause a compensatory increase in the background expression of other types of claudins, claudin-1, -2, -3, -4, -7, -12, -18, -20, and -23, in the small intestine. Cldn15(-/-) mice showed enhanced proliferation of normal cryptic cells after weaning without diseased states such as polyps or cancer, resulting in megaintestine, in which the upper small intestine was approximately 2 times larger than normal in length and diameter. The number of transit-amplifying cells in crypts increased approximately 2-fold. Freeze-fracture electron microscopy revealed that deficiency of claudin-15 decreased the number of TJ strands, although the electric conductance was decreased in distal segments in Cldn15(-/-) jejunum, as compared with Cldn15(+/+) littermates.
  
  
  CONCLUSIONS
  Based on the specific roles of claudins in paracellular barrier formation without any direct role in cell proliferation, as previously shown in cultured epithelial cells, we propose that claudin-15-based formation of TJs to organize the microenvironment including ion conductance is important for normal-sized morphogenesis of the small intestine.
authors.affiliation: Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Yamadaoka, Suita, Osaka, Japan. atsukita@biosci.med.osaka-u.ac.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tamura
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kitano
authors.forename: Masaki
authors.initials: M
authors.lastname: Hata
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Katsuno
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Moriwaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sasaki
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.forename: Mikio
authors.initials: M
authors.lastname: Furuse
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Tsukita
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tsukita
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D057167:Claudins; D004848:Epithelium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D017353:Gene Deletion; D007410:Intestinal Diseases / Q000235:genetics*; D007421:Intestine, Small / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D010641:Phenotype; D019108:Tight Junctions / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure
chemical_list: D057167:Claudins; D008565:Membrane Proteins; C459596:claudin 15