The TAM receptor tyrosine kinase Mer is expressed by cells of the retinal pigment epithelium (RPE), and genetic studies have demonstrated that Mer is essential for RPE function. RPE cells that lack Mer exhibit a severely compromised ability to phagocytose the distal ends of photoreceptor (PR) outer segments, which leads to the complete postnatal degeneration of photoreceptors and to blindness. Although in vitro experiments have implicated Gas6 as the critical TAM ligand for this process, we find that Gas6 mutant mice have a histologically intact retina with no photoreceptor degeneration. We further find that, in addition to Mer, RPE cells also express another TAM receptor - Tyro 3 - and that both of these receptors are instead activated independently by the Gas6-related ligand Protein S. This protein is also expressed by RPE cells. Finally, we demonstrate that loss of Mer function is accompanied by a substantial down-regulation in Tyro 3 as well. These observations indicate that both Mer and Tyro 3 act in mouse RPE cells and suggest that their biologically relevant ligand in these cells is Protein S.
Bibliographical noteFunding Information:
We thank Dan Gibbs and David Williams for advice and discussion on RPE biology and culture and Joe Hash for outstanding technical support. This work was supported by grants from the NIH and the Lupus Research Institute (G.L.) and from the Spanish Ministry of Education and Science (P.G.F.), and by fellowships from the Chapman Charitable Trust, the Legler Benbough Foundation, and the Timken-Sturgis Foundation (D.P.), the Pew Latin American Fellows Program (C.V.R.), and the Maximilian E. & Marion O. Hoffman Foundation (T.B-C.).