Abstract
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-CΔ196 transgenic epidermis, and provide a model for evaluation of aging-related skin changes.
Highlights
Formed during development by a series of cell commitment, mesenchymal-epithelial cell interactions, and terminal differentiation, the mammalian epidermis undergoes continuous self-renewal in a tightly regulated process of epidermal cell proliferation and differentiation [1,2,3]
We demonstrate that involucrin promoter (Inv)-Cldn6-CD196 mice display epidermal differentiation abnormalities at birth that result in slower epidermal maturation but are apparently normalized by 1-month of age
With aging, intrinsic properties of the Inv-Cldn6CD196 epidermis are manifested by a propensity for injury and inefficient repair, eventually resulting in chronic dermatitis especially in areas subjected to frequent insult via grooming
Summary
Formed during development by a series of cell commitment, mesenchymal-epithelial cell interactions, and terminal differentiation, the mammalian epidermis undergoes continuous self-renewal in a tightly regulated process of epidermal cell proliferation and differentiation [1,2,3]. As the end result of terminal differentiation, the robust barrier function of the skin protects against microorganism invasion and UV irradiation, inhibits water loss, regulates body temperature and is an important part of the host defense system [4]. These important functions decline in efficiency with aging, leading to an inefficient epidermal injury response and dermatitis [5,6,7], for reasons that are not yet understood. Inv-Cldn6-CD187 transgenic mice overexpressing a cytoplasmic tail-ablated Cldn display epidermal hyperproliferation, apparently due to an inefficiency of Cldn protein membrane targeting, as a result of the unfolded protein response pathway [17]
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