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.
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We acknowledge Dr. Amin Bredan for critical reading of the manuscript and the members of our research group for valuable discussions. We would also like to thank Prof. Dr. J. Ikenouchi (Kyoto University, Dept. of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering) for kindly providing us with the human occludin promoter construct. This research was funded by grants from V.I.B.-International PhD Program in Life Sciences, the FWO, the geconcerteerde onderzoeksacties of Ghent University, the Stichting tegen Kanker and the EU-FP7 framework program TuMIC 2008-201662.
Conflict of interest
The authors declare that they have no conflicts of interest.
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Tatari, M.N., De Craene, B., Soen, B. et al. ZEB2-transgene expression in the epidermis compromises the integrity of the epidermal barrier through the repression of different tight junction proteins. Cell. Mol. Life Sci. 71, 3599–3609 (2014). https://doi.org/10.1007/s00018-014-1589-0
- Tight junctions