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Qiutang Li, Patrick A. Scott, Henry J Kaplan, Douglas C Dean, Qingxian Lu; Novel function of β-catenin in RPE basal plasma membrane. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1919.
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B-catenin is a dual function protein, involved in gene transcription as the downstream effector of Wnt signaling and cell–cell adhesion by interacting with the cytoplasmic domain of cadherin. It mediates the adhesion function by recruiting α-catenin/actin cytoskeleton to membrane-bound P-, N-cadherins to form adhesion junctions. The cadherin/catenin complex plays an important role in maintaining epithelial integrity. Mutations in P-cadherin and α-catenin cause macular dystrophy but the pathogenic mechanisms remain unknown. It is unclear if β-catenin has any role in adult RPE. This study aims to dissect β-catenin function and its regulatory mechanism in adult RPE cells.
First, we examined cellular distribution of β-catenin and other major components of cadherin complexes in RPE. Then we generated a conditional knockout (cKO) of Ctnna1 (β-catenin) via Best1-promoter-Cre to examine β-catenin function in adult RPE. Two different mutations were examined - one only disrupted the nuclear transcription factor function of β-catenin and the other is a null mutation causing complete lack of β-catenin protein. We investigated the RPE cellular phenotype with: (1) Immunohistochemistry for markers delineating cell adhesion junction, RPE differentiation, cell polarity, microvilli organization; and (2) EM for ultrastructure.
Beyond the localization to cell-cell contacts, we found that cadherins, β-catenin, and α-catenin, localized to the basal plasma membrane in RPE. Conditional mutation of the transactivation domain of β-catenin in adult RPE did not have any obvious effect. However, the β-catenin null mutation led to loss of α-catenin from the RPE basal membrane and the affected RPE showed expansion and increased gaps between infolded basal plasma membranes and focal cell detachment from Bruch’s membrane. In contrast, the adhesion junction and recruitment of α-catenin at the lateral cell membrane were not disrupted. We further showed that the cadherin/catenin complex also localizes to the basal plasma membrane of human RPE.
B-catenin plays a critical role in maintenance of adult RPE morphology and stabilization of basal membrane infoldings. Our β-catenin cKO mice demonstrate many changes found in patients with mutations in P-cadherin or α-catenin. This β-catenin cKO mouse line may be an important model to study the etiology and pathogenesis of RPE dystrophy and macular degeneration.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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