Claudin-based tight junctions are crucial for the mammalian epidermal barrier

Abstract

The tight junction (TJ) and its adhesion molecules, claudins, are responsible for the barrier function of simple epithelia, but TJs have not been thought to play an important role in the barrier function of mammalian stratified epithelia, including the epidermis. Here we generated claudin-1–deficient mice and found that the animals died within 1 d of birth with wrinkled skin. Dehydration assay and transepidermal water loss measurements revealed that in these mice the epidermal barrier was severely affected, although the layered organization of keratinocytes appeared to be normal. These unexpected findings prompted us to reexamine TJs in the epidermis of wild-type mice. Close inspection by immunofluorescence microscopy with an antioccludin monoclonal antibody, a TJ-specific marker, identified continuous TJs in the stratum granulosum, where claudin-1 and -4 were concentrated. The occurrence of TJs was also confirmed by ultrathin section EM. In claudin-1–deficient mice, claudin-1 appeared to have simply been removed from these TJs, leaving occludin-positive (and also claudin-4–positive) TJs. Interestingly, in the wild-type epidermis these occludin-positive TJs efficiently prevented the diffusion of subcutaneously injected tracer (∼600 D) toward the skin surface, whereas in the claudin-1–deficient epidermis the tracer appeared to pass through these TJs. These findings provide the first evidence that continuous claudin-based TJs occur in the epidermis and that these TJs are crucial for the barrier function of the mammalian skin.

Claudin-1 and claudin-5 expression patterns differentiate lung squamous cell carcinomas from adenocarcinomas

“…27 Here we showed that CLDN-1 expression is high in lung squamous cell carcinomas (both by protein detection and transcript quantification), but reduced or undetected in adenocarcinomas. Interestingly, an increase in CLDN-1 expression was observed in keratinized regions of squamous cell carcinoma of the epidermis, 14 and in colon cancers, 28 whereas a decrease or loss of expression was reported in breast cancer cell lines 29,30 and tumors.…”

Claudin-1 overexpression in melanoma is regulated by PKC and contributes to melanoma cell motility

“…Claudin-4, although widely expressed in melanoma, was not as highly expressed as claudin-1 (Supplementary Figure 2b). This observation is interesting in the context of epidermal barrier integrity, as it has been shown that claudin-1 and -4 act together to form functional TJs in mammalian skin (Furuse et al, 2002). However, the high expression of claudin-1 did not appear to correlate to its normal function, as none of the melanoma cell lines had any functional TJs, as measured by a TER assay (Figure 2c).…”

“…Claudin proteins are known to directly interact with the zona occludens (ZO) proteins ZO-1, ZO-2 and ZO-3, and provide a critical structural component of the TJ (Heiskala et al, 2001). Claudin-1 and -4 have been shown to be important in the maintenance of barrier integrity in the epidermis, as claudin-1-deficient mice die within 1 day of birth, owing to defects in the epidermal barrier (Furuse et al, 2002).…”

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…157,158 In recent years, it has become evident that this most critical SC functionethe permeability barriereis impaired in most ichthyosis forms. 11,60,[159][160][161][162][163][164] Several murine knockout models for ichthyosis [Spink5 (e/e), Tgm1 (e/e), Abca12 (e/e) mice, [165][166][167] Alox12b (e/e), 168 Cldn1(e/e) 169 ] have demonstrated neonatal lethality as a result of dehydration, underscoring the critical role of these genes in permeability barrier competence. Mutations that either alter the lipid composition of the SC membranesedisorders of lipid metabolismeor affect the function of the corneocyte structural proteinsedisorders of keratinocyte proteinseresult in increased water movement through the intercellular pathway.…”