Establishment of Two Mouse Models for CEDNIK Syndrome Reveals the Pivotal Role of SNAP29 in Epidermal Differentiation.
Establishment of Two Mouse Models for CEDNIK Syndrome Reveals the Pivotal Role of SNAP29 in Epidermal Differentiation.
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DOI：
10.1016/j.jid.2015.12.020
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发表时间：
2016-03
期刊：
影响因子：
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通讯作者：
S. Schiller;Christina Seebode;Georg L. Wieser;S. Goebbels;W. Möbius;M. Horowitz;O. Sarig;E. Sprecher;S. Emmert
中科院分区：
文献类型：
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作者：
S. Schiller;Christina Seebode;Georg L. Wieser;S. Goebbels;W. Möbius;M. Horowitz;O. Sarig;E. Sprecher;S. Emmert
突触体相关蛋白29（SNAP 29）基因的功能缺失突变导致脑发育不全、神经病、鱼鳞病和角化病综合征。在这项研究中，我们创建了总（Snap 29-/-）以及角质形成细胞特异性（Snap 29 fl/fl/K14-Cre）Snap 29敲除小鼠。两种突变小鼠均表现出先天性独特的鱼鳞病表型，导致新生儿死亡。突变小鼠表现出棘皮症和角化过度以及异常角质形成细胞分化和增殖增加。此外，表皮屏障严重受损。这些结果表明SNAP 29在表皮分化和屏障形成中的重要作用。突变小鼠表皮中板层体内容物沉积显着减少以及畸形板层体的观察表明，由于Snap 29敲除，板层体功能严重受损。我们还发现增加的微管相关蛋白-1轻链3，亚型B-II水平，不变的p62/SQSTM 1蛋白量，并强烈诱导内质网应激标志物C/EBP同源蛋白在突变小鼠。这强调了SNAP 29在自噬和内质网应激中的作用。我们的小鼠模型是研究角质形成细胞分化过程的有力工具，并提供了SNAP 29对表皮分化的重要贡献的见解。
Loss-of-function mutations in the synaptosomal-associated protein 29 (SNAP29) gene cause the cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome. In this study, we created total (Snap29–/–) as well as keratinocyte-specific (Snap29fl/fl/K14-Cre)Snap29knockout mice. Both mutant mice exhibited a congenital distinct ichthyotic phenotype resulting in neonatal lethality. Mutant mice revealed acanthosis and hyperkeratosis as well as abnormal keratinocyte differentiation and increased proliferation. In addition, the epidermal barrier was severely impaired. These results indicate an essential role of SNAP29 in epidermal differentiation and barrier formation. Markedly decreased deposition of lamellar body contents in mutant mice epidermis and the observation of malformed lamellar bodies indicate severe impairments in lamellar body function due to theSnap29knockout. We also found increased microtubule associated protein-1 light chain 3, isoform B-II levels, unchanged p62/SQSTM1 protein amounts, and strong induction of the endoplasmic reticulum stress marker C/EBP homologous protein in mutant mice. This emphasizes a role of SNAP29 in autophagy and endoplasmic reticulum stress. Our murine models serve as powerful tools for investigating keratinocyte differentiation processes and provide insights into the essential contribution of SNAP29 to epidermal differentiation.