A Drosophila Model of Epidermolysis Bullosa Simplex.
A Drosophila Model of Epidermolysis Bullosa Simplex.
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DOI：
10.1038/jid.2015.129
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发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Magin TM
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文献类型：
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作者：
Bohnekamp J;Cryderman DE;Paululat A;Baccam GC;Wallrath LL;Magin TM
水疱性皮肤病单纯性大疱性表皮病（EBS）是由编码基底表皮角质形成细胞中间丝网络的K5或K14基因的显性突变引起的。由于EBS突变导致的角蛋白网络形成和崩溃的机制仍不完全清楚。果蝇缺乏细胞质中间丝，提供了一个“空”的环境来检查角蛋白网络的形成，并确定突变角蛋白引起病理的机制。在这里，我们报告说，无处不在的共表达的转基因编码野生型人类K14和K5导致广泛的角蛋白网络的形成在果蝇上皮和非上皮组织，造成没有明显的表型。与哺乳动物细胞相似，用磷酸酶抑制剂处理转基因果蝇组织引起角蛋白网络崩溃，验证果蝇作为研究角蛋白动力学的遗传模型系统。K5和K14 R125 C突变体的共表达导致最严重形式的EBS，导致在上皮和非上皮苍蝇组织中广泛形成EBS样细胞质角蛋白聚集体。K14 R125 C/K5的表达导致半致死性;成年幸存者发展翅膀水泡，并不能飞，由于缺乏细胞间粘附在翼心发展。这种果蝇EBS模型对于鉴定突变角蛋白改变的途径和开发EBS治疗方法是有价值的。
The blistering skin disorder Epidermolysis bullosa simplex (EBS) results from dominant mutations in K5 or K14 genes, encoding the intermediate filament network of basal epidermal keratinocytes. The mechanisms governing keratin network formation and collapse due to EBS mutations remain incompletely understood. Drosophila lacks cytoplasmic intermediate filaments, providing a ‚null’ environment to examine the formation of keratin networks and determine mechanisms by which mutant keratins cause pathology. Here, we report that ubiquitous co-expression of transgenes encoding wild-type human K14 and K5 resulted in the formation of extensive keratin networks in Drosophila epithelial and non-epithelial tissues, causing no overt phenotype. Similar to mammalian cells, treatment of transgenic fly tissues with phosphatase inhibitors caused keratin network collapse, validating Drosophila as a genetic model system to investigate keratin dynamics. Co-expression of K5 and a K14R125C mutant that causes the most severe form of EBS resulted in widespread formation of EBS-like cytoplasmic keratin aggregates in epithelial and non-epithelial fly tissues. Expression of K14R125C/K5 caused semi-lethality; adult survivors developed wing blisters and were flightless due to lack of intercellular adhesion during wing heart development. This Drosophila model of EBS is valuable for the identification of pathways altered by mutant keratins and for development of EBS therapies.