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Tal Burstyn-Cohen, Greg Lemke; Protein S Is A Mer Ligand For Rpe-mediated Phagocytosis Of Photoreceptors In-vivo. Invest. Ophthalmol. Vis. Sci. 2011;52(14):903.
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The daily Phagocytosis of photoreceptor outer segments is essential for retinal viability, and is mediated by the Mer tyrosine kinase receptor. Mutations in Mer are implicated in retinal degeneration in mice, rats and humans. The two ligands that bind and activate Mer are Gas6 and Protein S (ProS). In-vitro experiments suggested that Gas6 is the relevant ligand, however Gas6 KO mice do not exhibit retinal degeneration. The hypothesis that ProS is a ligand for Mer-mediated photoreceptor phagocytosis was put to test.
We generated a conditional KO mouse for ProS to investigate its role in retinal homeostasis. We generated two mouse lines mediating ProS deletion in RPE cells, and in the neural retina, and analyzed these eyes for retinal degeneration by histology. We also generated double ProS and Gas6 KO mice to address potential ligand redundancy.
ProS-deleted eyes showed only mild photoreceptor degeneration. Mice with ProS deleted in RPE cells presented with peripheral degeneration, while central degeneration of photoreceptors was observed when ProS was deleted from the neural retina. When both Gas6 and ProS ligands were deleted, complete retinal degeneration was observed at 2 months, similar to that observed in Mer KO mice.
We have generated a conditional KO mouse model for ProS. Using this mouse model, we show that ProS is a biologically functional ligand for the Mer receptor tyrosine kinase, with a key role in maintaining retinal homeostasis. Our results suggest that ProS and Gas6 act in concert to activate Mer, allowing for successful phagocytosis essential to maintain retinal homeostasis. These results provide mechanistic insight on RPE-mediated phagocytosis of photoreceptors through Mer. We propose further research to test possible involvement of ProS in retinal degenerative pathologies.
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