Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice.
Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice.
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DOI：
10.1083/jcb.200110122
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发表时间：
2002-03-18
影响因子：
7.8
通讯作者：
Tsukita, Shoichiro
中科院分区：
文献类型：
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作者：
Furuse, Mikio;Hata, Masaki;Furuse, Kyoko;Yoshida, Yoko;Haratake, Akinori;Sugitani, Yoshinobu;Noda, Tetsuo;Kubo, Akiharu;Tsukita, Shoichiro
紧密连接（TJ）及其黏附分子克劳丁蛋白对单层上皮的屏障功能起作用，但一直认为TJ在包括表皮在内的哺乳动物复层上皮的屏障功能中并不起重要作用。在此我们培育出克劳丁 - 1基因缺陷型小鼠，发现这些小鼠出生1天内死亡，皮肤起皱。脱水实验和经表皮水分流失测量显示，尽管角质形成细胞的分层结构看似正常，但这些小鼠的表皮屏障受到严重影响。这些意外的发现促使我们重新检查野生型小鼠表皮中的TJ。用抗闭合蛋白单克隆抗体（一种TJ特异性标记物）进行免疫荧光显微镜仔细观察，在颗粒层发现连续的TJ，克劳丁 - 1和克劳丁 - 4集中在此处。超薄切片电子显微镜也证实了TJ的存在。在克劳丁 - 1缺陷型小鼠中，克劳丁 - 1似乎只是从这些TJ中缺失了，留下闭合蛋白阳性（克劳丁 - 4也阳性）的TJ。有趣的是，在野生型表皮中，这些闭合蛋白阳性的TJ能有效阻止皮下注射的示踪剂（约600道尔顿）向皮肤表面扩散，而在克劳丁 - 1缺陷型表皮中，示踪剂似乎能穿过这些TJ。这些发现首次证明基于克劳丁的连续TJ存在于表皮中，且这些TJ对哺乳动物皮肤的屏障功能至关重要。
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-1–deficient 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-1–deficient mice, claudin-1 appeared to have simply been removed from these TJs, leaving occludin-positive (and also claudin-4–positive) 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-1–deficient 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.