Megaintestine in claudin-15-deficient mice

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 134; no. 2; p. 523
• Main Authors: Tamura, Atsushi, Kitano, Yuka, Hata, Masaki, Katsuno, Tatsuya, Moriwaki, Kazumasa, Sasaki, Hiroyuki, Hayashi, Hisayoshi, Suzuki, Yuichi, Noda, Tetsuo, Furuse, Mikio, Tsukita, Shoichiro, Tsukita, Sachiko
• Format: Journal Article
• Language: English
• Published: United States 01.02.2008
• Subjects: Animals; Cell Proliferation; Claudins; Epithelium - metabolism; Epithelium - pathology; Epithelium - ultrastructure; Gene Deletion; Intestinal Diseases - genetics; Intestine, Small - growth & development; Intestine, Small - metabolism; Intestine, Small - pathology; Intestine, Small - ultrastructure; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Phenotype; Tight Junctions - metabolism; Tight Junctions - pathology; Tight Junctions - ultrastructure
• ISSN: 1528-0012
• DOI: 10.1053/j.gastro.2007.11.040

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. 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. 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. 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.