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Catherine Cheng, Xiaohua Gong; Ephrin-A5 and EphA2 regulate lens development and cataract formation through distinct mechanisms. Invest. Ophthalmol. Vis. Sci. 2013;54(15):461.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the roles of Eph/ephrin signaling in lens development and cataractogenesis.
Using ephrin-A5 knockout (-/-) and EphA2(-/-) mice, we characterized lens phenotypes using confocal images of GFP-positive lens epithelial and fiber cells. Cell-cell junctions and adhesion and cytoskeletal structures were examined by immunohistochemistry.
Ephrin-A5(-/-) lenses often developed anterior cataracts associated with clusters of epithelial cells undergoing the epithelial-to-mesenchymal transition, and changes in E-cadherin and β-catenin staining indicated cell-cell junction alterations. Unexpectedly, anterior epithelial cells of EphA2(-/-) lenses showed no obvious changes, but equatorial epithelial cells failed to form precisely aligned meridional rows. Immunostaining revealed that EphA2, β-actin, total and phosphorylated cortactin and phosphorylated Src were enriched at the vertices of wild-type (WT) hexagon-shaped equatorial epithelial cells organized into meridional rows. In disorganized EphA2(-/-) equatorial epithelial cells, β-actin and total cortactin formed abnormal clusters, and there was a loss of phosphorylated cortactin and Src. In addition, E-cadherin junctions, which were normally localized at basal-lateral ends of WT equatorial epithelial cells but diminished in newly differentiating fibers, became widely distributed on all sides of EphA2(-/-) epithelial cells and persisted in fiber cells. The presence of EphA2 was essential for activating Src and localizing E-cadherin and F-actin at the lens fulcrum where the apical ends of differentiating epithelial cells became constricted before fiber cell differentiation and elongation.
Loss of ephrin-A5 causes obvious changes in anterior epithelial cells, indicating that ephrin-A5 is essential for maintaining the morphology and polarity of anterior epithelial cells. In contrast, EphA2 organizes Src/cortactin/F-actin complexes at the basal-lateral vertices of hexagon-shaped equatorial epithelial cells and controls Src/E-cadherin/F-actin localization at the lens fulcrum. These changes in epithelial cells are likely to be early events that lead to cataracts in ephrin-A5(-/-) and EphA2(-/-) lenses. The phenotypic difference between ephrin-A5(-/-) and EphA2(-/-) lenses suggests that these two molecules are not a receptor-ligand pair in the lens.
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