Involucrin–claudin-6 tail deletion mutant (C206) transgenic mice: a model of delayed epidermal permeability barrier formation and repair

The prevalence of preterm birth is widespread with very little understanding of its causes and no unambiguous epidemiological data for predicting its occurrence. Formed in weeks 30 to 33 of pregnancy (Wilson and Maibach, 1980), the protective epidermal permeability barrier (EPB) of the skin is essential for survival as it provides the first line of defense against infection, environmental insult, and the loss of heat and solutes (Baharestani, 2007; Gibson et al., 2006; Shwayder and Akland, 2005; Soll, 2008). In infants born before 32 weeks of pregnancy, severe EPB dysfunction may result in death or long-term complications (Pilling et al., 2008). The EPB is formed in the later stages of epidermal terminal differentiation, and consists of tight junction (TJ) strands of adjacent cells that associate laterally (Brandner, 2009; Brandner et al., 2002; Langbein et al., 2002; Langbein et al., 2003; Schluter et al., 2007; Turksen and Troy, 2002) and function in sealing intracellular spaces for paracellular diffusion control (Farquhar and Palade, 1963). The selective permeability of the EPB is provided by a family of 23 highly conserved integral membrane proteins known as claudins (Cldns), a relatively recently identified component of TJs (Angelow et al., 2008; Chiba et al., 2008; Findley and Koval, 2009; Krause et al., 2008; Turksen and Troy, 2004; Van Itallie and Anderson, 2006). Heterogeneity within the Cldn family results from distinctly charged amino acid sequences within the first external loop; thus, the specific permeability properties of different epithelia are attributed to their different Cldn compositions (Daugherty et al., 2007; Katoh, 2003; Krause et al., 2008; Turksen and Troy, 2004). Recent studies have clearly demonstrated that Cldn-containing TJs are intricately involved in epidermal differentiation programs, and that TJ function, and thus barrier integrity, is modified in response to Cldn modulation (Arabzadeh et al., 2006; Furuse et al., 2002; Troy et al., 2005b; Troy and Turksen, 2007; Turksen and Troy, 2002). For instance, Cldn1 knockout mice die shortly after birth owing to EPB dysfunction (Furuse et al., 2002). Inv-Cldn6 transgenic mice, in which the involucrin (Inv) promoter targets Cldn6 to the suprabasal layers of the epidermis, also suffer EPB abnormalities with a phenotype mimicking that seen in premature human babies, the severity/lethality of which is dependent upon the level of Cldn6 overexpression (Troy et al., 2005b; Turksen and Troy, 2002). Inefficient membrane targeting of Cldn proteins and a highly proliferative epidermal phenotype – apparently as a result of the unfolded protein response pathway – were observed upon overexpression of a cytoplasmic tail-ablated Cldn6 (Inv-Cldn6C187) in mice (Arabzadeh et al., 2006). Furthermore, dependent on the level of overexpression, Inv-Cldn6-C196 mice (with half the cytoplasmic tail ablated) (Troy and Turksen, 2007) displayed EPB RESEARCH ARTICLE