Abstract
Recent genetic studies show that the Eph/ephrin bidirectional signaling pathway is associated with both congenital and age-related cataracts in mice and humans. We have investigated the molecular mechanisms of cataractogenesis and the roles of ephrin-A5 and EphA2 in the lens. Ephrin-A5 knockout (-/-) mice often display anterior polar cataracts while EphA2(-/-) lenses show very mild cortical or nuclear cataracts at weaning age. The anterior polar cataract of ephrin-A5(-/-) lenses is correlated with multilayers of aberrant cells that express alpha smooth muscle actin, a marker for mesenchymal cells. Only select fiber cells are altered in ephrin-A5(-/-) lenses. Moreover, the disruption of membrane-associated β-catenin and E-cadherin junctions is observed in ephrin-A5(-/-) lens central epithelial cells. In contrast, EphA2(-/-) lenses display normal monolayer epithelium while disorganization is apparent in all lens fiber cells. Immunostaining of ephrin-A5 proteins, highly expressed in lens epithelial cells, were not colocalized with EphA2 proteins, mainly expressed in lens fiber cells. Besides the previously reported function of ephrin-A5 in lens fiber cells, this work suggests that ephrin-A5 regulates β-catenin signaling and E-cadherin to prevent lens anterior epithelial cells from undergoing the epithelial-to-mesenchymal transition while EphA2 is essential for controlling the organization of lens fiber cells through an unknown mechanism. Ephrin-A5 and EphA2 likely interacting with other members of Eph/ephrin family to play diverse functions in lens epithelial cells and/or fiber cells.
Highlights
The lens is comprised of a monolayer of epithelial cells that covers the anterior hemisphere of bulk elongated fibers, wrapped by a basement membrane called the lens capsule
We have found that ephrin-A5 is important for maintaining anterior lens epithelial cells and that EphA2 is essential for the organization of lens fiber cells
Ephrin-A5 and EphA2 are mainly segregated in the lens In order to further elucidate molecular basis for the diverse functions between ephrin-A5 and EphA2 in the lens, we examined whether ephrin-A5 and EphA2 proteins were colocalized in lens epithelial cells and/or newly differentiating fiber cells by using immunohistochemical analysis on lens capsule flat mounts
Summary
The lens is comprised of a monolayer of epithelial cells that covers the anterior hemisphere of bulk elongated fibers, wrapped by a basement membrane called the lens capsule. Lifelong lens growth depends upon a small population of epithelial cells located slightly anterior to the equator in what is known as the circumferential germinative zone. Epithelial cells in the germinative zone continuously proliferate and differentiate into elongating fiber cells at the lens equator [1,2]. The majority of anterior epithelial cells, known as central epithelial cells, remain mitotically inactive and stay in close contact with underlying elongating fiber cells via the apical interface [3,4]. The epithelialfiber cell interaction exists until the elongating fiber cells reach the anterior suture where the tips of opposing elongating fibers meet each other and detach from the anterior epithelial cells [5]. The spatial and temporal regulation of epithelial cells is essential for regulating lens growth and homeostasis [6,7]
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