Novel function of beta-catenin in regulation of RPE basal membrane

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PROJECT SUMMARY/ABSTRACT The RPE acts as a blood outer retinal barrier transporting nutrients from the choroid circulation to adjacent photoreceptors. Apical microvilli on the RPE are critical for interdigitating interaction with photoreceptor outer segments. The basal membrane of the RPE differentiates into a heavily folded plasma membrane system to form a specialized organelle, called basal infolding. These infoldings dramatically increases the surface area to enhance diffusion and transporter-assisted flux of solutes, factors, nutrients, and metabolites. How the infolding arises and its potential relevance to RPE biology has not been explored. In preliminary results, we demonstrate that this infolding is mediated by -catenin in a complex with N- and P-cadherins/-catenin, and cytoplasmic - catenin is required for the integrity of basal membrane infolding. We hypothesize that the increase in surface area resulting from membrane infolding is critical for efficient nutrient transport. Similar membrane infolding increases surface area at the blood brain barrier, the intestinal lumen and kidney tubules that serve as a blood- urine barrier. Consistent with functional inhibition of nutrient transport, mouse -catenin mutants show shortening of adjacent photoreceptor outer segments, which depend upon nutrients transported through the RPE. In this proposal, we will test whether the -catenin/cadherin complex stabilizes the RPE basal infoldings for maintaining the basal infolding integrity and ensuring efficient transport of nutrients and metabolites across the RPE barrier. Inadequate metabolic support from RPE has been linked to several aspects of age-related macular degeneration, as have mutations in P-cadherin and α-catenin. As such, the β-catenin conditional knockout mouse represents an important model to study the etiology and pathogenesis of RPE dystrophy and retinal degeneration. Our study will provide a novel mechanism for the integrity of RPE basal infoldings and its relevance to RPE function, which may give insight into the pathogenesis of RPE dystrophy and AMD, even some of renal diseases.