Lack of Plakoglobin in Epidermis Leads to Keratoderma
Lack of Plakoglobin in Epidermis Leads to Keratoderma
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DOI：
10.1074/jbc.m111.299669
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发表时间：
2012-03-23
影响因子：
4.8
通讯作者：
Shou, Weinian
中科院分区：
文献类型：
--
作者：
Li, Deqiang;Zhang, Wenjun;Shou, Weinian
Jup的功能丧失突变与Naxos病相关，Naxos病的特征是致炎性心肌病和皮肤疾病掌跖角化病。以前，我们已经表明，在小鼠心肌细胞中基因消融Jup会导致类似于人类Naxos病的致瘤性心肌病。目前，为了确定Naxos病相关性角化病的发病机制，我们通过在角质形成细胞中限制性灭活Jup来产生Jup突变小鼠。Jup突变小鼠在很大程度上再现了人类掌跖角化病的临床特征：表皮过度角化和增厚。Jup突变小鼠也遭受皮肤溃疡和炎症。细胞凋亡和增殖在Jup突变体表皮显着增加。超微结构分析显示，中断的装配桥粒和adherens Jup突变体表皮连接。我们还证明了β-连环蛋白在Jup突变细胞-细胞连接处的补偿性增加，而不改变其信号传导活性。我们的研究结果提供了重要的见解，了解人类掌跖角化病的发病机制。
Loss-of-function mutation of Jup has been associated with Naxos disease, which is characterized by arrhythmogenic cardiomyopathy and the cutaneous disorder palmoplantar keratoderma. Previously, we have shown that genetic ablation of Jup in cardiomyocytes in mice leads to arrhythmogenic cardiomyopathy similar to Naxos disease in humans. Currently, to determine the pathogenesis of Naxos disease-associated keratoderma, we generated Jup mutant mice by inactivating Jup restrictively in keratinocytes. Jup mutant mice largely recapitulated the clinical features of human palmoplantar keratoderma: overcornification and thickening of the epidermis. Jup mutant mice also suffered skin ulceration and inflammation. Cell apoptosis and proliferation were significantly elevated in Jup mutant epidermis. Ultrastructural analyses revealed the disruption of the assembly of desmosomes and adherens junctions in Jup mutant epidermis. We also demonstrated the compensational increase in beta-catenin at Jup mutant cell-cell junctions without altering its signaling activities. Our findings provide important insights for understanding the pathogenesis of human palmoplantar keratoderma.