Sprott Centre for Stem Cell Research at the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
PLoS One. 2009 Nov 13;4(11):e7814. doi: 10.1371/journal.pone.0007814.
The barrier function of the skin protects the mammalian body against infection, dehydration, UV irradiation and temperature fluctuation. Barrier function is reduced with the skin's intrinsic aging process, however the molecular mechanisms involved are unknown. We previously demonstrated that Claudin (Cldn)-containing tight junctions (TJs) are essential in the development of the epidermis and that transgenic mice overexpressing Cldn6 in the suprabasal layers of the epidermis undergo a perturbed terminal differentiation program characterized in part by reduced barrier function. To dissect further the mechanisms by which Cldn6 acts during epithelial differentiation, we overexpressed a Cldn6 cytoplasmic tail deletion mutant in the suprabasal compartment of the transgenic mouse epidermis. Although there were no gross phenotypic abnormalities at birth, subtle epidermal anomalies were present that disappeared by one month of age, indicative of a robust injury response. However, with aging, epidermal changes with eventual chronic dermatitis appeared with a concomitant barrier dysfunction manifested in increased trans-epidermal water loss. Immunohistochemical analysis revealed aberrant suprabasal Cldn localization with marked down-regulation of Cldn1. Both the proliferative and terminal differentiation compartments were perturbed as evidenced by mislocalization of multiple epidermal markers. These results suggest that the normally robust injury response mechanism of the epidermis is lost in the aging Involucrin-Cldn6-CDelta196 transgenic epidermis, and provide a model for evaluation of aging-related skin changes.
皮肤的屏障功能可保护哺乳动物机体免受感染、脱水、UV 辐射和温度波动的影响。皮肤的固有老化过程会降低其屏障功能，但涉及的分子机制尚不清楚。我们之前的研究表明，Claudin（Cldn）包含的紧密连接（TJs）对于表皮的发育至关重要，并且在表皮的基底层过度表达 Cldn6 的转基因小鼠会经历一个紊乱的终末分化程序，其特征部分是屏障功能降低。为了进一步剖析 Cldn6 在上皮细胞分化过程中的作用机制，我们在转基因小鼠表皮的基底层过表达了 Cldn6 细胞质尾部缺失突变体。尽管出生时没有明显的表型异常，但存在细微的表皮异常，一个月大时这些异常消失，表明存在强大的损伤反应。然而，随着年龄的增长，出现了表皮变化，最终出现慢性皮炎，同时伴随着屏障功能障碍，表现为经表皮水分流失增加。免疫组织化学分析显示，Cldn1 的表达明显下调，导致 Cldn 的超基底层定位异常。多个表皮标志物的定位异常表明增殖和终末分化区室均受到干扰。这些结果表明，在老化的 involucrin-Cldn6-CDelta196 转基因表皮中，表皮正常的强大损伤反应机制丧失，并为评估与年龄相关的皮肤变化提供了模型。
