Center for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany.
Center for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
J Invest Dermatol. 2021 Nov;141(11):2602-2610.e3. doi: 10.1016/j.jid.2021.04.008. Epub 2021 May 7.
The skin epidermis is attached to the underlying dermis by a laminin 332 (Lm332)-rich basement membrane. Consequently, loss of Lm332 leads to the severe blistering disorder epidermolysis bullosa junctionalis in humans and animals. Owing to the indispensable role of Lm332 in keratinocyte adhesion in vivo, the severity of the disease has limited research into other functions of the protein. We have conditionally disrupted Lm332 expression in basal keratinocytes of adult mice. Although blisters develop along the interfollicular epidermis, hair follicle basal cells provide sufficient anchorage of the epidermis to the dermis, making inducible deletion of the Lama3 gene compatible with life. Loss of Lm332 promoted the thickening of the epidermis and exaggerated desquamation. Global RNA expression analysis revealed major changes in the expression of keratins, cornified envelope proteins, and cellular stress markers. These modifications of the keratinocyte genetic program are accompanied by changes in cell shape and disorganization of the actin cytoskeleton. These data indicate that loss of Lm332-mediated progenitor cell adhesion alters cell fate and disturbs epidermal homeostasis.
皮肤表皮通过富含层粘连蛋白 332（Lm332）的基底膜附着在下面的真皮上。因此，Lm332 的缺失会导致人类和动物中严重的水疱性交界性大疱性表皮松解症。由于 Lm332 在角质形成细胞黏附中具有不可或缺的作用，因此该疾病的严重程度限制了对该蛋白其他功能的研究。我们已经在成年小鼠的基底角质形成细胞中条件性地破坏了 Lm332 的表达。尽管水疱沿着毛囊间表皮形成，但毛囊基底细胞为表皮与真皮提供了足够的锚定，使得 Lama3 基因的诱导性缺失与生命相容。Lm332 的缺失促进了表皮的增厚和过度脱屑。全局 RNA 表达分析显示角蛋白、角质包膜蛋白和细胞应激标志物的表达发生了重大变化。角质形成细胞遗传程序的这些改变伴随着细胞形状的改变和肌动蛋白细胞骨架的紊乱。这些数据表明，缺失 Lm332 介导的祖细胞黏附会改变细胞命运并扰乱表皮稳态。
