Abstract
The retinal pigment epithelium (RPE) supports the health and function of retinal photoreceptors and is essential for normal vision. RPE cells are post-mitotic, terminally differentiated, and polarized epithelial cells. In pathological conditions, however, they lose their epithelial integrity, become dysfunctional, even dedifferentiate, and ultimately die. The integrity of epithelial cells is maintained, in part, by adherens junctions, which are composed of cadherin homodimers and p120-, β-, and α-catenins linking to actin filaments. While E-cadherin is the major cadherin for forming the epithelial phenotype in most epithelial cell types, it has been reported that cadherin expression in RPE cells is different from other epithelial cells based on results with cultured RPE cells. In this study, we revisited the expression of cadherins in the RPE to clarify their relative contribution by measuring the absolute quantity of cDNAs produced from mRNAs of three classical cadherins (E-, N-, and P-cadherins) in the RPE in vivo. We found that P-cadherin (CDH3) is highly dominant in both mouse and human RPE in situ. The degree of dominance of P-cadherin is surprisingly large, with mouse Cdh3 and human CDH3 accounting for 82–85% and 92–93% of the total of the three cadherin mRNAs, respectively. We confirmed the expression of P-cadherin protein at the cell-cell border of mouse RPE in situ by immunofluorescence. Furthermore, we found that oxidative stress induces dissociation of P-cadherin and β-catenin from the cell membrane and subsequent translocation of β-catenin into the nucleus, resulting in activation of the canonical Wnt/β-catenin pathway. This is the first report of absolute comparison of the expression of three cadherins in the RPE, and the results suggest that the physiological role of P-cadherin in the RPE needs to be reevaluated.
Highlights
The retinal pigment epithelium (RPE), located between retinal photoreceptor cells and the choroid of the eye, is a single layer of pigmented epithelial cells with cobblestone-like morphology [1]
As in the case of mouse RPE, these results clearly show that CDH3 is the vastly dominant cadherin expressed in human RPE in situ at the mRNA level, with CDH3 accounting for 92~93% of the total of the three cadherin expression
After observing that oxidative stress resulted in a dramatic change in the distribution of P-cadherin in mouse RPE, we investigated the localization of β-catenin, another component of adherens junctions as well as a key factor of the Wnt/β-catenin signaling pathway
Summary
The retinal pigment epithelium (RPE), located between retinal photoreceptor cells and the choroid of the eye, is a single layer of pigmented epithelial cells with cobblestone-like morphology [1]. RPE cells are known to dedifferentiate and lose their fully matured state as a result of a variety of stresses, including oxidative stress and mechanical dissociation of cell-cell junctions [4,5,6,7,8,9,10]. Dissociation of cultured RPE cells leads to dedifferentiation of the cells into fibroblast-like cells through epithelial to mesenchymal transition (EMT) [5, 9]. EMT is a process in which cells lose cell-cell junctions and epithelial morphology and become fibroblast-like with increased mesenchymal markers [11,12,13]. RPE cells undergoing EMT contribute to scarring and wound contractions in proliferative vitreoretinopathy (PVR) as well as subretinal fibrosis in advanced AMD [14,15,16]
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