The interaction of the retinal pigment epithelium (RPE) with the underlying photoreceptors (PR) is vital for the survival of these photosensitive cells. When this process is defective, death of the PR ensues, accompanied by progressive vision loss, as in the RCS rat. In this animal, the RPE is unable to perform its normal function of phagocytosing the shed tips of PRs, leading to death of these cells. It has recently been shown that the defective gene in the RCS rat codes for a specific receptor tyrosine kinase (RTK), Mertk. Mertk on the apical surface of the RPE interacts with the shed tips of PR outer segments (OS) via a signaling molecule, Gas6. The interaction of Gas6 with Mertk, and the downstream biochemical events that eventually lead to the ingestion of the shed tips of OS will be the focus of the proposed studies. ? ? Experiments are proposed to investigate: a) the source of Gas6 in the eye; b) its production in relation to the L/D cycle; c) its interaction with the OS plasma membrane; d) its interaction with Mertk using isolated OS and RPE cells grown in tissue culture; e) the intracellular downstream biochemical events that eventually lead to the ingestion of OS, using cultured RPE cells transfected with adenovirus vectors carrying either dominant active or dominant negative forms of components of the RTK signaling pathway. Pharmacological agents that affect various steps in the signaling pathway will also be used. ? ? It has recently been shown that a mutation in Mertk leads to a form of retinitis pigmentosa in humans, demonstrating that the biochemical pathway that is responsible for the phagocytosis of shed OS by the RPE is crucial to the survival of the PRs. It is thus very likely that mutations in any of the various steps governing this process would also be detrimental to vision. By describing the complete biochemical pathway controlling OS phagocytosis by RPE cells, we will provide a base for other researchers to study the possible role of each of the steps of this pathway in retinal defects in humans.
| Burgess, Barry L; Abrams, Toshka A; Nagata, Shigekazu et al. (2006) MFG-E8 in the retina and retinal pigment epithelium of rat and mouse. Mol Vis 12:1437-47 |
| Hall, Michael O; Obin, Martin S; Heeb, Mary J et al. (2005) Both protein S and Gas6 stimulate outer segment phagocytosis by cultured rat retinal pigment epithelial cells. Exp Eye Res 81:581-91 |
