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 ∼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.