Macular and retinal degeneration are common blinding conditions which affect approximately 30% of individuals aged 75 years, and pose considerable socioeconomic burden. Lack of the daily phagocytosis of photoreceptor outer segments (POS) by Retinal Pigment Epithelium (RPE) cells is the basis of such retinal degeneration (RD). This proposal aims to characterize the role of TAM receptor Tyrosine Kinase signaling in maintaining healthy retinal homeostasis. TAM receptors (Tyro3, Axl, Mer) are homeostatic regulators of the Immune, Reproductive and Nervous systems. Mer knockout mice show normal retinal structure at birth; however, at three weeks of age photoreceptors (PRs) begin to undergo apoptotic death, and by 8 weeks the entire PR population is eliminated, causing blindness. Mer mutations in rats and humans, leads to impaired vision and blindness. The two TAM ligands ProS and Gas6 are expressed in the eye. In-vitro experiments have identified Gas6 as the relevant ligand necessary to activate PR phagocytosis, but adult Gas6 KO mice have no PR degeneration, suggesting a role for ProS. To investigate whether ProS is a TAM agonist leading to PR phagocytosis, I developed a unique ProS conditional knockout mouse model. Preliminary results indicate that mice lacking ProS in the eyes show mild RD, suggesting ProS is a functional ligand in-vivo. Deleting both ligands causes severe RD, implying synergism between both ligands. This novel evidence illuminates the mechanism of TAM signaling in-vivo suggesting ligand hetero-dimerization. Using the newly generated mouse model, I propose to characterize the detailed expression pattern of TAM receptors and ligands in the eye, to establish a role for ProS in retinal homeostasis, and to utilize the unique model to better understand the TAM signaling mechanism. A linkage between ligand levels and RD will be tested, and if found, ProS and Gas6 may serve as early biomarkers for retinal degenerative disease.