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Abstract
Ectodysplasin A (Eda), a member of the tumour necrosis factor superfamily, plays an important role in ectodermal organ development. An EDA mutation underlies the most common of ectodermal dysplasias, that is X‐linked hypohidrotic ectodermal dysplasia (XLHED) in humans. Even though it lacks a developmental function, the role of Eda during the postnatal stage remains elusive. In this study, we found tight junctional proteins ZO‐1 and claudin‐1 expression is largely reduced in epidermal, corneal and lung epithelia in Eda mutant Tabby mice at different postnatal ages. These declines are associated with tail ulceration, corneal pannus formation and lung infection. Furthermore, topical application of recombinant Eda protein markedly mitigated corneal barrier dysfunction. Using cultures of a human corneal epithelial cell line and Tabby mouse skin tissue explants, Eda up‐regulated expression of ZO‐1 and claudin‐1 through activation of the sonic hedgehog signalling pathway. We conclude that EDA gene expression contributes to the maintenance of epithelial barrier function. Such insight may help efforts to identify novel strategies for improving management of XLHED disease manifestations in a clinical setting.
Highlights
Ectodysplasin A (Eda) is a member of the tumour necrosis factor (TNF) superfamily regulating ectodermal development in various organs
We show here that epithelial tight junctional integrity is compromised in the cornea, skin and lung of Tabby mice, which was accompanied by abnormal ZO-1 and claudin-1 protein expression leading to epithelial barrier dysfunction
Even though it is known that the Eda gene has a developmental function in controlling the morphogenesis of various ectodermal structures such as hair, teeth, nails and exocrine glands, little is known about its postnatal function
Summary
Eda is a member of the tumour necrosis factor (TNF) superfamily regulating ectodermal development in various organs. Germline EDA mutations cause a syndrome designated as XLHED characterized by the absence or malformation of multiple ectodermal appendages resulting in hypotrichosis, hypodontia, anhidrosis or hypohidrosis [1,2,3,4]. XLHED-afflicted individuals in their youth are at increased risk for developing severe, acute pneumonia and respiratory infections [2, 8]. It was presumed that exocrine gland insufficiencies of the respiratory tract [8, 13, 14] and skin surface [10] could lead to chronic inflammatory and recurrent infection.
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