Published online 11 March 2002. doi:10.1083/jcb.200110122
© The Rockefeller University Press,
0021-9525/2002/3/1099 $5.00
The Journal of Cell Biology, Volume 156, Number 6, March 18, 2002 1099-1111
Claudin-based tight junctions are crucial for the mammalian epidermal barrier
:
a lesson from claudin-1deficient mice
Mikio Furuse1,
Masaki Hata2,
Kyoko Furuse2,
Yoko Yoshida3,
Akinori Haratake4,
Yoshinobu Sugitani5,
Tetsuo Noda5,6,
Akiharu Kubo1 and
Shoichiro Tsukita1
1 Department of Cell Biology, Kyoto University Faculty of Medicine, Yoshida-Konoe, Sakyo-ku, Kyoto 606-8501, Japan
2 KAN Research Institute, Inc., Kyoto Research Park, Chudoji, Shimogyo-ku, Kyoto 600-8317, Japan
3 Department of Dermatology, Kyoto University Faculty of Medicine, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
4 Basic Research Laboratory, Kanebo, Ltd., Kotobuki-cho, Odawara, Kanagawa 250-0002, Japan
5 Department of Cell Biology, Japanese Foundation for Cancer Research-Cancer Institute, Kami-Ikebukuro, Toshima-ku, Tokyo 170-8455, Japan
6 Department of Molecular Genetics, Tohoku University School of Medicine, Seryo-cho, Aoba-ku, Sendai 980-8575, Japan
Address correspondence to Shoichiro Tsukita, Dept. of Cell Biology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Tel.: 81-75-753-4372. Fax: 81-75-753-4660. E-mail: htsukita{at}mfour.med.kyoto-u.ac.jp
The tight junction (TJ) and its adhesion molecules, claudins, are responsible for the barrier function of simple epithelia, but TJs have not been thought to play an important role in the barrier function of mammalian stratified epithelia, including the epidermis. Here we generated claudin-1deficient mice and found that the animals died within 1 d of birth with wrinkled skin. Dehydration assay and transepidermal water loss measurements revealed that in these mice the epidermal barrier was severely affected, although the layered organization of keratinocytes appeared to be normal. These unexpected findings prompted us to reexamine TJs in the epidermis of wild-type mice. Close inspection by immunofluorescence microscopy with an antioccludin monoclonal antibody, a TJ-specific marker, identified continuous TJs in the stratum granulosum, where claudin-1 and -4 were concentrated. The occurrence of TJs was also confirmed by ultrathin section EM. In claudin-1deficient mice, claudin-1 appeared to have simply been removed from these TJs, leaving occludin-positive (and also claudin-4positive) TJs. Interestingly, in the wild-type epidermis these occludin-positive TJs efficiently prevented the diffusion of subcutaneously injected tracer (
600 D) toward the skin surface, whereas in the claudin-1deficient epidermis the tracer appeared to pass through these TJs. These findings provide the first evidence that continuous claudin-based TJs occur in the epidermis and that these TJs are crucial for the barrier function of the mammalian skin.
Key Words: claudin-1; tight junction; skin; epidermis; barrier

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