Tight junctions are well-developed between adjacent endothelial cells of blood vessels in the central nervous system, and play a central role in establishing the blood-brain barrier (BBB). Claudin-5 is a major cell adhesion molecule of tight junctions in brain endothelial cells. To examine its possible involvement in the BBB, claudin-5–deficient mice were generated. In the brains of these mice, the development and morphology of blood vessels were not altered, showing no bleeding or edema. However, tracer experiments and magnetic resonance imaging revealed that in these mice, the BBB against small molecules (<800 D), but not larger molecules, was selectively affected. This unexpected finding (i.e., the size-selective loosening of the BBB) not only provides new insight into the basic molecular physiology of BBB but also opens a new way to deliver potential drugs across the BBB into the central nervous system.
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12 May 2003
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May 12 2003
Size-selective loosening of the blood-brain barrier in claudin-5–deficient mice
Takehiro Nitta,
Takehiro Nitta
1Department of Cell Biology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
2Department of Neurosurgery, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
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Masaki Hata,
Masaki Hata
3KAN Research Institute, Kyoto Research Park, Shimogyo-ku, Kyoto 606-8317, Japan
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Shimpei Gotoh,
Shimpei Gotoh
1Department of Cell Biology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
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Yoshiteru Seo,
Yoshiteru Seo
4Department of Physiology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-0841, Japan
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Hiroyuki Sasaki,
Hiroyuki Sasaki
3KAN Research Institute, Kyoto Research Park, Shimogyo-ku, Kyoto 606-8317, Japan
5Department of Molecular Cell Biology, Institute of DNA Medicine, Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan
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Nobuo Hashimoto,
Nobuo Hashimoto
2Department of Neurosurgery, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
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Mikio Furuse,
Mikio Furuse
1Department of Cell Biology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
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Shoichiro Tsukita
Shoichiro Tsukita
1Department of Cell Biology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
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Takehiro Nitta
1Department of Cell Biology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
2Department of Neurosurgery, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
Masaki Hata
3KAN Research Institute, Kyoto Research Park, Shimogyo-ku, Kyoto 606-8317, Japan
Shimpei Gotoh
1Department of Cell Biology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Yoshiteru Seo
4Department of Physiology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-0841, Japan
Hiroyuki Sasaki
3KAN Research Institute, Kyoto Research Park, Shimogyo-ku, Kyoto 606-8317, Japan
5Department of Molecular Cell Biology, Institute of DNA Medicine, Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan
Nobuo Hashimoto
2Department of Neurosurgery, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan
Mikio Furuse
1Department of Cell Biology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Shoichiro Tsukita
1Department of Cell Biology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Address correspondence to Shoichiro Tsukita, Dept. of Cell Biology, Faculty of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto 606-8501, Japan. Tel.: 81-75-753-4372. Fax: 81-75-753-4660. E-mail: [email protected]
*
Abbreviations used in this paper: BBB, blood-brain barrier; Cld, claudin; CNS, central nervous system; ES, embryonic stem; Gd-DTPA, gadolinium–diethylene triamine-N,N,N′,N″,N″-pentaacetic acid; MRI, magnetic resonance imaging; pAb, polyclonal antibody; TJ, tight junction.
Received:
February 11 2003
Revision Received:
March 18 2003
Accepted:
March 26 2003
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2003
J Cell Biol (2003) 161 (3): 653–660.
Article history
Received:
February 11 2003
Revision Received:
March 18 2003
Accepted:
March 26 2003
Citation
Takehiro Nitta, Masaki Hata, Shimpei Gotoh, Yoshiteru Seo, Hiroyuki Sasaki, Nobuo Hashimoto, Mikio Furuse, Shoichiro Tsukita; Size-selective loosening of the blood-brain barrier in claudin-5–deficient mice . J Cell Biol 12 May 2003; 161 (3): 653–660. doi: https://doi.org/10.1083/jcb.200302070
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