An estimated 28% of the 4 million annual neonatal deaths are because of preterm birth. It is likely that many of these deaths result from an immature permeability barrier, leading to dehydration and infection with associated septic shock. The statistics published by the March of Dimes indicate a 36% increase in premature births in America in the last 25 years, and the cause is not understood. This is an alarming, and emotionally and ethically complex, situation that adds significant pressure to pediatric medicine. The absence of appropriate disease models in which to delineate the basis of barrier dysfunction and test new therapies limits progress in the field.

Here, the authors characterize a mouse model that mimics a debilitating, non-fatal form of a dysfunctional epidermal permeability barrier, similar to that seen in human premature babies. The tight junction-associated proteins, claudins, play a crucial role in estabilishing the epidermal permeability barrier. One theory is that claudin-containing tight junctions act as command centers in which the claudin extracellular loops influence selective permeability, while their cytoplasmic tail domains send signals to other receptors to coordinate downstream effectors, such as the cytoskeleton. The transgenic mouse reported here contains a short claudin 6 tail truncation. This mutation results in a delayed and defective epidermal permeability barrier that, surprisingly, is repaired within 2–4 days after birth. The repair process was associated with remodeling of the claudin 1 expression domains that eliminated the defective differentiated epidermal cells and replaced them with apparently ‘normal’ and terminally differentiated epidermal cells. The trigger for repair appears to be exposure to air. The potential signaling pathways involved include the sphingosine-1-phosphate (S1P) pathway and preliminary observations implicate Erk1/2 downstream of the S1P-receptor 2. The relevance of this model for understanding human disease is confirmed by the authors’ observations of similar features in specimens from premature babies, including dramatic delays in barrier formation and dysregulation of claudin expression, notably claudin 1.

Clinical outcomes for premature babies have been improved by using incubators that carefully control heat and humidity, but currently there are no therapeutic approaches for accelerating repair of the premature epidermal permeability barrier. The observation that activation of S1P and S1P-receptor 2 induce permeability repair processes suggests the therapeutic potential of selective receptor agonists. A few agonists have been described and this model is a viable model to test them. In summary, we think it is important to have made a model that mimics a repairable human epidermal permeability barrier, to have documented important cellular mechanisms of that repair, and to have begun delineation of the underlying molecular mechanisms, which are also pointing towards potential new therapies.