Claudin-1 is a p63 target gene with a crucial role in epithelial development.
Claudin-1 is a p63 target gene with a crucial role in epithelial development.
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DOI：
10.1371/journal.pone.0002715
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发表时间：
2008-07-23
期刊：
影响因子：
3.7
通讯作者：
Guerrini L
中科院分区：
文献类型：
--
作者：
Lopardo T;Lo Iacono N;Marinari B;Giustizieri ML;Cyr DG;Merlo G;Crosti F;Costanzo A;Guerrini L
皮肤的表皮是一种自我更新的复层上皮，起着人体和外部环境之间的接口作用，并起到防止水分流失的作用。细胞间连接的成分，如克劳丁，对保持组织完整性和水分保持至关重要。P63是干细胞增殖和上皮复层所必需的转录因子，在以外胚层发育不良为特征的人类遗传性综合征中发生突变。P63和Claudin-1基因缺失的小鼠在出生后几个小时内都会因为严重的皮肤异常而脱水而死亡。这些观察表明，这两个基因可能在一个调控途径上与p63相连，可能调控Claudin-1的表达。在这里，我们表明，在原代小鼠角质形成细胞中沉默ClaudinNp63导致Δ-1表达显著下调(−80%)。ΔNp63α在体内与Claudin-1启动子结合并激活内源性Claudin-1基因和含有Claudin-1基因-1.4kb启动子片段的报告载体。因此，在E15.5 p63基因缺失小鼠的皮肤中没有Claudin-1的表达，并且天然的p63突变蛋白，特别是那些在强直-外胚层发育不良-剥离(AEC)患者中发现的蛋白，在调节Claudin-1转录的能力上确实发生了改变。这与携带I537T p63突变的AEC患者表皮中Claudin-1的表达缺陷有关。值得注意的是，AEC患者的皮肤脆性与Claudin-1和p63基因缺失小鼠的表皮相似。这些发现证实了这两个基因可能在共同的调控途径中相连的假设，并且Claudin-1可能是参与外胚层发育不良发病机制的一个重要的p63靶基因。
The epidermis of the skin is a self-renewing, stratified epithelium that functions as the interface between the human body and the outer environment, and acts as a barrier to water loss. Components of intercellular junctions, such as Claudins, are critical to maintain tissue integrity and water retention. p63 is a transcription factor essential for proliferation of stem cells and for stratification in epithelia, mutated in human hereditary syndromes characterized by ectodermal dysplasia. Both p63 and Claudin-1 null mice die within few hours from birth due to dehydration from severe skin abnormalities. These observations suggested the possibility that these two genes might be linked in one regulatory pathway with p63 possibly regulating Claudin-1 expression. Here we show that silencing of ΔNp63 in primary mouse keratinocytes results in a marked down-regulation of Claudin-1 expression (−80%). ΔNp63α binds in vivo to the Claudin-1 promoter and activates both the endogenous Claudin-1 gene and a reporter vector containing a –1.4 Kb promoter fragment of the Claudin-1 gene. Accordingly, Claudin-1 expression was absent in the skin of E15.5 p63 null mice and natural p63 mutant proteins, specifically those found in Ankyloblepharon–Ectodermal dysplasia–Clefting (AEC) patients, were indeed altered in their capacity to regulate Claudin-1 transcription. This correlates with deficient Claudin-1 expression in the epidermis of an AEC patient carrying the I537T p63 mutation. Notably, AEC patients display skin fragility similar to what observed in the epidermis of Claudin-1 and p63 null mice. These findings reinforce the hypothesis that these two genes might be linked in a common regulatory pathway and that Claudin-1 may is an important p63 target gene involved in the pathogenesis of ectodermal dysplasias.
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影响因子：
7.8
作者：
Furuse, Mikio;Hata, Masaki;Furuse, Kyoko;Yoshida, Yoko;Haratake, Akinori;Sugitani, Yoshinobu;Noda, Tetsuo;Kubo, Akiharu;Tsukita, Shoichiro
通讯作者：
Tsukita, Shoichiro
影响因子：
2.6
作者：
Levi, G;Mantero, S;Merlo, GR
通讯作者：
Merlo, GR
影响因子：
64.8
作者：
Mills, AA;Zheng, BH;Bradley, A
通讯作者：
Bradley, A
影响因子：
3.6
作者：
Dufresne, Julie;Cyr, Daniel G.
通讯作者：
Cyr, Daniel G.
单个基因产物Claudin -1或-2，在成纤维细胞中重构紧密结合的连接链和新兵。
影响因子：
7.8
作者：
Furuse, M;Sasaki, H;Fujimoto, K;Tsukita, S
通讯作者：
Tsukita, S