Abstract
The eye lens is responsible for fine focusing of light onto the retina, and its function relies on tissue transparency and biomechanical properties. Recent studies have demonstrated the importance of Eph-ephrin signaling for the maintenance of life-long lens homeostasis. The binding of Eph receptor tyrosine kinases to ephrin ligands leads to a bidirectional signaling pathway that controls many cellular processes. In particular, dysfunction of the receptor EphA2 or the ligand ephrin-A5 lead to a variety of congenital and age-related cataracts, defined as any opacity in the lens, in human patients. In addition, a wealth of animal studies reveal the unique and overlapping functions of EphA2 and ephrin-A5 in lens cell shape, cell organization and patterning, and overall tissue optical and biomechanical properties. Significant differences in lens phenotypes of mouse models with disrupted EphA2 or ephrin-A5 signaling indicate that genetic modifiers likely affect cataract phenotypes and progression, suggesting a possible reason for the variability of human cataracts due to Eph-ephrin dysfunction. This review summarizes the roles of EphA2 and ephrin-A5 in the lens and suggests future avenues of study.
Highlights
Erythropoietin-producing hepatocellular carcinoma (Eph)-ephrin signaling plays an important role in development, homeostasis, and disease in humans (Henkemeyer et al, 1994; Holmberg et al, 2000; Clevers and Batlle, 2006; Zhao et al, 2006) and other organisms (Park et al, 2004; Picco et al, 2007; Lisabeth et al, 2013)
Ephrin-A5−/− anterior epithelial cells showed punctate, rather than membranelocalized, β-catenin immunostaining signals along with abnormal E-cadherin staining (Cheng and Gong, 2011). These defects in cell-cell adhesion through adherens junctions likely lead to EMT, and the cluster of abnormal anterior epithelial cells invade the underlying fiber cell layer to cause anterior cataracts in the ephrin-A5−/− mice (Figures 3B,C) (Cheng and Gong, 2011)
The expression of EphA2 receptor proteins in the lens was identified at equatorial epithelial cell and fiber cell membranes and in fiber cell tips (Figure 3A) (Jun et al, 2009; Cheng and Gong, 2011; Cheng et al, 2017; Zhou and Shiels, 2018)
Summary
Eph-ephrin signaling plays an important role in development, homeostasis, and disease in humans (Henkemeyer et al, 1994; Holmberg et al, 2000; Clevers and Batlle, 2006; Zhao et al, 2006) and other organisms (Park et al, 2004; Picco et al, 2007; Lisabeth et al, 2013). Ephrin-A5−/− mice in a mixed genetic (129/Sv:C57BL/6) background have severe and nearly whole cataracts at 6 months of age with posterior capsule rupture, and lenses from younger mice have many cellular abnormalities, including vacuoles and alterations in the fiber cell shape, size, organization, and packing
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