Time- and dose-dependent claudin contribution to biological functions: Lessons from claudin-1 in skin

There are many types of biologic compartments in the body. Tight junctions (TJs) function to create a dynamic paracellular barrier to separate these compartments and maintain homeostasis. The TJ component claudin-1 is the major transmembrane protein responsible for forming the paracellular barrier in the epidermis; other claudins in the epidermis include claudin-3, -4, -12, -23 and -25. Accumulating evidence points to a relationship between claudin-1 and skin diseases; for example, a decrease in claudin-1 is reported in human atopic dermatitis. However, how claudin-1 directly or indirectly contributes to disease in the context of the paracellular barrier is poorly understood. We recently established several mouse lines in which the claudin-1 expression was systematically regulated, and showed that claudin-1 time- and dose-dependently regulates epidermis function and disease in vivo. In this commentary, we will discuss recent progress on this topic, including our latest findings, and remaining or newly arisen issues