Cadherins in the retinal pigment epithelium (RPE) revisited: P-cadherin is the highly dominant cadherin expressed in human and mouse RPE in vivo

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.

Functional Voltage-Gated Calcium Channels Are Present in Human Embryonic Stem Cell-Derived Retinal Pigment Epithelium

“…We used mouse RPE as the native counterpart for hESC‐RPE in our studies due to unavailability of live human RPE tissue. Previous work on gene and protein expression profiles of human and mouse RPE show high similarity regarding general biological functions, canonical pathways, and molecular networks . However, there are important species‐specific differences between human and mouse RPE.…”

Polarity and epithelial-mesenchymal transition of retinal pigment epithelial cells in proliferative vitreoretinopathy

“…In quiescent adult RPE cells, epithelial cadherins (E- and/or P-cadherin) sequester β-catenin at the AJs to maintain cell–cell contact. Reduction of cadherin levels or dissociation of AJs allows β-catenin to translocate into the nucleus, where it interacts with the transcription factor LEF, and activates the transcription of various genes, including Snail and cyclin D1, which participate in RPE cell EMT via the canonical Wnt/β-catenin signaling pathway ( Gonzalez & Medici, 2014 ; Lamouille, Xu & Derynck, 2014 ; Nelson & Nusse, 2004 ; Yang et al, 2018 ) . Tamiya, Liu & Kaplan (2010) suggested that the loss of P-cadherin causes the loss of cell–cell contact and initiates RPE cell migration and EMT.…”

Peer Review #1 of "Polarity and epithelial-mesenchymal transition of retinal pigment epithelial cells in proliferative vitreoretinopathy (v0.1)"

“…In quiescent adult RPE cells, epithelial cadherins (E-and/or P-cadherin) sequester β-catenin at the AJs to maintain cell-cell contact. Reduction of cadherin levels or dissociation of AJs allows β-catenin to translocate into the nucleus, where it interacts with the transcription factor LEF, and activates the transcription of various genes, including Snail and cyclin D1, which participate in RPE cell EMT via the canonical Wnt/β-catenin signaling pathway (Gonzalez & Medici 2014;Lamouille et al 2014;Nelson & Nusse 2004;Yang et al 2018) . Tamiya et al (2010) suggested that the loss of Pcadherin causes the loss of cell-cell contact and initiates RPE cell migration and EMT.…”