Regulation of Mer tyrosine kinase receptor activity in synchronized daily retinal phagocytosis – MERACTI

At the back of the eye lies a monolayer of cells essential for vision: the retinal pigment epithelium (RPE). Apical microvilli from these polarized cells make close contact with the outer segment of photoreceptors, the cells capturing light photons and initiating visual phototransduction. RPE cells ensure various functions: supply of nutrients to photoreceptors, renewal of photopigments,… One of their main role is the phagocytosis of photoreceptor outer segments (POS). Indeed, photoreceptors renew their outer segments constantly to fight the high levels of oxidative damage they are subjected to. In order to keep cell length even, POS shed their most distal tip everyday following a circadian rhythm. These extremities are immediately phagocytosed by adjacent RPE cells.
We recently demonstrated that alphavbeta5 integrin receptors bind POS and synchronize phagocytosis. Additionally, we showed that the Mer tyrosine kinase (MerTK) receptor is necessary for internalization of POS bound at the RPE apical cell surface. Absence or deregulation of retinal phagocytosis lead to the developpement of blinding diseases, such as early-onset retinitis pigmentosa or age-related macular degeneration (AMD), first cause of blindness after 50 years in industrialized countries. Moreover, MERTK mutations have been detected in cone-rod dystrophy patients. In addition, our latest data show a role of both the full MerTK protein and a soluble form of MerTK in regulating POS phagocytosis.
Despite its obvious importance, regulation of MerTK activity during POS phagocytosis by RPE cells remains poorly understood. The MERACTI project focuses on the characterization of MerTK activity to internalize POS rhythmically. We plan on identifying all the important factors for proper MerTK function, such as implication of soluble MerTK, intracellular domains of the protein and downstream signaling pathways. These will be analyzed both in vitro and in vivo, using multiple approaches and 2 new animal models.
Understanding how proteins network and interact to complete daily this crucial task will enlight us on normal retinal function and on the consequences of phagocytic defects in the retina. This will help us consider therapeutic targets for these pathologies for which no treatment exists up to this date.