Abstract
Abstract: :
Purpose:RAGE, the receptor for advanced glycation end (AGE) products, is expressed in several cell types during development, downregulated at completion, and then re–expressed during the course of aging pathologies. These events are regulated, in part, through altered levels of RAGE ligands during both development and pathogenesis. One such ligand, S100B, is expressed in the CNS, but its role in the retina is poorly understood. Based on the reported upregulation of RAGE in 1) RPE cells associated with AGE product deposition and histopathology in aging and AMD maculas, and 2) in S100B retinal overexpressing transgenic mice showing abnormal RPE cells and a slow photoreceptor degeneration, we propose that reexpression of RAGE may affect the differentiation status of the RPE and contribute to pathogenesis in the aging eye. In order to characterize the role of S100B, RAGE, and another RAGE ligand, amphoterin, on RPE cell differentiation we examined the expression of these proteins during RPE development in the murine eye. Methods: Monspecific antibodies for S100B, amphoterin, RAGE, and CRALBP were used to immunolabel cells during murine retinal development. Expression was examined in 1) wildtype mice, 2) transgenic mice expressing the EGFP reporter under the regulation of the S100B promoter, and 3) S100B overexpressing transgenic mice at E15, E17, P2, P6, P8, P10, P13 and adult time points. The non–secreted EGFP tagged mice allows for identification of cell specific expression. Results: While S100B immunolabels cells throughout the retina, EGFP mice revealed expression only in Muller cells and some ganglion cells. During embryonic stages, the RPE exhibits EGFP signal, not present in adult mice. S100B, amphoterin and RAGE immunolabeling show an overlapping spatial and temporal localization in the RPE at E17 coincident with immunolabeling for the early RPE differentiation marker, CRALBP. S100B adult transgenic mice exhibit significant immunolabeling for S100B, RAGE and the myofibroblast marker– αSMA in the RPE which is not present in wildtype and EGFP tagged mice. Conclusions:Preliminary studies show that S100B, amphoterin and RAGE may play a role in RPE cell development and differentiation similar to that reported for other cell types. We will continue these studies to examine ligand/RAGE mediated RPE cell differentiation and additional effects of S100B overexpression, AGE products, and sustained RAGE expression on RPE differentiation status.
Keywords: retinal pigment epithelium • retinal development • age-related macular degeneration