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D.E. Cosgrove, G. Bhattacharya, D. Meehan, D. Delimont, M.A. Gratton, W. Kimberling, D. Birch; Usherin binds integrins on RPE cells and may mediate adhesion and cellular homeostasis. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):2483.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Usher syndrome type IIa is the most common (>50% of cases) of the 11 eleven different molecular subtypes associated with Usher syndrome, the predominant genetic cause of combined deafness and blindness in first–world countries. The gene was identified and its product characterized as a novel basement membrane protein abundant in both structural and vascular basement membranes of the cochlea and retina, but also found in many other non–pathologic organs. This study aimed to understand how usherin functions in basement membranes of the retina, and to provide clues regarding the mechanism of USH2A pathophysiology. Methods: Co–immunoprecipitation using recombinant usherin and plasma membrane preparations from ARPE–19 cells, cell adhesion studies with integrin blocking antibodies, and immunofluorescence analysis were used to identify usherin receptors RPE cells. Usherin knockout mice and integrin knockout mice were analyzed physiologically and by TEM. Results: Usherin binds specifically to integrins a1b1, a3b1, and a5b1 on ARPE19 cells, and these integrins localize to the basolateral aspect of the RPE in rat retinas. Integrin a1 knockout mice develop ultrastructural defects in the RPE by 9 months of age. Usherin knockout mice show defects much earlier, and unlike the a1 integrin receptor knockouts, show ultrastructural defects in the RPE microvilli, and appear to have a defect in adhesion to the basement membrane of Bruch's layer. Preliminary electroretinograms suggest a visual deficit in the usherin knockout mice. Conclusions: Usherin may function in the retina as a substrate for RPE cell adhesion and signaling via interaction with specific integrin receptors on the RPE cell surface.
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