ZEB2-transgene expression in the epidermis compromises the integrity of the epidermal barrier through the repression of different tight junction proteins

Abstract

Epithelial homeostasis within the epidermis is maintained by means of multiple cell-cell adhesion complexes such as adherens junctions, tight junctions, gap junctions, and desmosomes. These complexes co-operate in the formation and the regulation of the epidermal barrier. Disruption of the epidermal barrier through the deregulation of the above complexes is the cause behind a number of skin disorders such as psoriasis, dermatitis, keratosis, and others. During epithelial-to-mesenchymal transition (EMT), epithelial cells lose their adhesive capacities and gain mesenchymal properties. ZEB transcription factors are key inducers of EMT. In order to gain a better understanding of the functional role of ZEB2 in epidermal homeostasis, we generated a mouse model with conditional overexpression of Zeb2 in the epidermis. Our analysis revealed that Zeb2 expression in the epidermis leads to hyperproliferation due to the combined downregulation of different tight junction proteins compromising the epidermal barrier. Using two epidermis-specific in vivo models and in vitro promoter assays, we identified occludin as a new Zeb2 target gene. Immunohistological analysis performed on human skin biopsies covering various pathogeneses revealed ZEB2 expression in the epidermis of pemphigus vulgaris. Collectively, our data support the notion for a potential role of ZEB2 in intracellular signaling of this disease.

Terminal NK cell maturation is controlled by concerted actions of T-bet and Zeb2 and is essential for melanoma rejection

“…For this purpose, NK cell maturation intermediates were defined as shown in Fig. 1 Tg/Tg mice (Tatari et al, 2014). These genetic modifications allow selective inactivation of Zeb2 or transgenic (Tg) Zeb2 expression from the Rosa26 promoter in NK cells, respectively.…”

Epidermal tight junctions in health and disease

“…19 In addition to the already large number of TJ proteins identified in human or mouse epidermis, some TJ proteins have been identified only in cultured keratinocytes ( Table 2). Further studies are needed to 118 were also found in the SC of mice. determine their expression patterns in a fully developed mature epidermis.…”

Scaffolding proteins in the development and maintenance of the epidermal permeability barrier

“…claudins 1, 7, and 12, Junctional Adhesion Molecule (JAM)-A, and MUPP1), or to the spinous keratinocytes (e.g., ZO-1, ZO-2, claudins 4, 6, 18). [26][27][28]35,[57][58][59][60][61][62] Similar to observations in cultured keratinocytes, disruption of cadherin-containing adherens junctions in vivo results in impairment in tight junction formation. Targeted inactivation of Cdh1 in mice, which encodes E-cadherin, results in extensive transepidermal water loss and loss of functional tight junctions in the stratum granulosum.…”