Abstract
The EDA gene encodes ectodysplasin A (Eda), which if mutated causes X-linked hypohidrotic ectodermal dysplasia (XLHED) disease in humans. Ocular surface changes occur in XLHED patients whereas its underlying mechanism remains elusive. In this study, we found Eda was highly expressed in meibomian glands, and it was detected in human tears but not serum. Corneal epithelial integrity was defective and the thickness was reduced in the early postnatal stage of Eda mutant Tabby mice. Corneal epithelial cell proliferation decreased and the epithelial wound healing was delayed in Tabby mice, whereas it was restored by exogenous Eda. Eda exposure promoted mouse corneal epithelial wound healing during organ culture, whereas scratch wound assay showed that it did not affect human corneal epithelial cell line migration. Epidermal growth factor receptor (EGFR), phosphorylated EGFR (p-EGFR), and phosphorylated ERK1/2 (p-ERK) were down-regulated in Tabby mice corneal epithelium. Eda treatment up-regulated the expression of Ki67, EGFR, p-EGFR, and p-ERK in human corneal epithelial cells in a dose-dependent manner. In conclusion, Eda protein can be secreted from meibomian glands and promotes corneal epithelial cell proliferation through regulation of the EGFR signaling pathway. Eda release into the tears plays an essential role in the maintenance of corneal epithelial homeostasis.
Highlights
Ectodysplasin A (Eda)3 is a type II transmembrane protein belonging to the tumor necrosis factor (TNF) superfamily
Meibomian gland development is dependent on ectodysplasin A (Eda) gene expression because in Tabby mice, a natural Eda mutation resulted in no meibomian gland morphogenesis [18]
Based on Eda being a secretory protein, we proposed that Eda protein could be secreted from the meibomian glands into the tears and targeted to the ocular surface epithelium
Summary
Along with the corneal epithelial defect in this EDA mutant, meibomian gland development is severely retarded in XLHED patients. Ocular surface abnormalities such as dry eye, chronic conjunctivitis, and blepharitis become evident during the early childhood of these patients and gradually progresses with age [15, 16]. Our recent study showed that pathological ocular surface changes in 6 – 8-week-old Tabby mice resembled those described in meibomian gland dysfunctional evaporative dry eye patients [19]. We found an earlier report in which ectopic Eda gene expression in Tabby mice rescued to a large extent ocular surface abnormalities, despite absence of meibomian gland development in the EDA gene knock-in mice [18].
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