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X. Gong, C. Cheng, D. Feldheim, S. Wang; Disruption of Eph-ephrin Signaling in Lens Epithelial Cells Causes Age-related Cataracts. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1223.
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To investigate the mechanism for how disruption of Eph-ephirn signaling leads to age-related cataracts in humans and mice, and to study the roles of Eph-ephrin and Map kinases in the lens during development by using ephrinA5 knockout mice and Map kinase transgenic mice.
GFP transgene was introduced into ephrinA5 knockout mice and Map kinase transgenic mice by breeding with a GFP transgenic mouse line. GFP-positive epithelial and fiber cells of fresh lenses of these mice were imaged by a Leica confocal microscopy. Lens phenotypes were examined by histology and immunohistochemistry.
EphrinA5(-/-) mice had variable lens phenotypes (or cataracts). A phenotypic difference can be observed occasionally between left and right lenses of an ephrinA5(-/-) mouse. Approximately 20% of ephrinA5(-/-) had mild cortical or nuclear cataracts while most of these mutant lenses remained clear at three weeks of age. However, lens epithelial cells of all ephrinA5(-/-) mice had significant changes in cell morphology and in cell-cell contacts, such as increased extracellular space. Some epithelial cells were appeared abnormally in the underlying lens fiber cell areas. Differentiating fiber cells appear to elongate properly in young ephrinA5(-/-) lenses. EphrinA5(-/-) lenses with cataracts had severe defects in the epithelial cells and cortical fibers. Immunohistochemistry demonstrated the changes of epithelial cell polarity markers, such as ZO-1 and other adhesion molecules.
The loss of ephrinA5 causes dramatic changes in lens epithelial cell, indicating that ephrinA5 signaling is essential for maintaining the morphology, polarity and communication of epithelial cells. These changes in the epithelial cells, rather than fiber cells, are likely to be early events that lead to age-related cataracts in ephrinA5(-/-) lenses. Presumably, altered epithelial cells cannot maintain epithelial-epithelial and epithelial-fiber communication that is crucial for the homeostasis of lens fiber cells. Map kinase may be mediated the downstream changes of Eph-ephrin signalling.
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