Annexin A8 regulates Wnt signaling to maintain the phenotypic plasticity of retinal pigment epithelial cells.

ABSTRACT: Wnt signalling mediates complex cell-cellinteractions during development and proliferation. Annexin A8 (AnxA8), a calcium-dependent phospholipid-binding protein, and canonical Wnt signalling mechanisms have both been implicated in retinal pigment epithelial (RPE) cell differentiation. The aim here was to examine the possibility of cross-talk between AnxA8 and Wnt signalling, as both are down-regulated upon fenretinide (FR)-mediated RPE transdifferentiation. AnxA8 suppression in RPE cells via siRNA or administration of FR induced neuronal-like cell transdifferentiation and reduced expression of Wnt-related genes, as measured by real-time PCR and western blotting. AnxA8 gene expression, on the other hand, remained unaltered upon manipulating Wnt signalling, suggesting Wnt-related genes to be downstream effectors of AnxA8. Co-immunoprecipitation revealed an interaction between AnxA8 and ?-catenin, which was reduced in the presence of activated TGF-?1. TGF-?1 signalling also reversed the AnxA8 loss-induced cell morphology changes, and induced ?-catenin translocation and GSK-3? phosphorylation in the absence of AnxA8. Ectopic over-expression of AnxA8 led to an increase in active ?-catenin and GSK-3? phosphorylation. These data demonstrate an important role for AnxA8 as a regulator of Wnt signalling and a determinant of RPE phenotype, with implications for regenerative medicine approaches that utilise stem cell-derived RPE cells to treat conditions such as age-related macular degeneration.

SUBMITTER: Lueck K 

PROVIDER: S-EPMC6985107 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature