Abstract
SummaryMaintenance of a healthy photoreceptor-retinal pigment epithelium (RPE) interface is essential for vision. At the center of this interface, apical membrane protrusions stemming from the RPE ensheath photoreceptor outer segments (POS), and are possibly involved in the recycling of POS through phagocytosis. The molecules that regulate POS ensheathment and its relationship to phagocytosis remain to be deciphered. By means of ultrastructural analysis, we revealed that Mer receptor tyrosine kinase (MERTK) ligands, GAS6 and PROS1, rather than αVβ5 integrin receptor ligands, triggered POS ensheathment by human embryonic stem cell (hESC)-derived RPE. Furthermore, we found that ensheathment is required for POS fragmentation before internalization. Consistently, POS ensheathment, fragmentation, and internalization were abolished in MERTK mutant RPE, and rescue of MERTK expression in retinitis pigmentosa (RP38) patient RPE counteracted these defects. Our results suggest that loss of ensheathment due to MERTK dysfunction might contribute to vision impairment in RP38 patients.
Highlights
The retinal pigment epithelium (RPE) is a monolayer of pigmented epithelial cells that are essential for the function and survival of the overlying retinal photoreceptors and for the preservation of vision
At the center of this interface, apical membrane protrusions stemming from the RPE ensheath photoreceptor outer segments (POS), and are possibly involved in the recycling of POS through phagocytosis
By means of ultrastructural analysis, we revealed that Mer receptor tyrosine kinase (MERTK) ligands, growth arrest-specific protein 6 (GAS6) and PROS1, rather than aVb5 integrin receptor ligands, triggered POS ensheathment by human embryonic stem cell-derived RPE
Summary
The retinal pigment epithelium (RPE) is a monolayer of pigmented epithelial cells that are essential for the function and survival of the overlying retinal photoreceptors and for the preservation of vision. POS renewal and clearance are required to avoid accumulation of oxidized lipids and light-damaged proteins in the IPM and for the recycling of molecules involved in the light cycle (Strauss, 2005). It remains unclear whether POS are actively shed by photoreceptors, removed by extrinsic processes, or a combination of both. In vivo histology studies showed that ensheathing RPE membranes invade POS structure, possibly during or before POS separation, suggesting that RPE might be ‘‘biting-off’’ POS tips, which could be part of the phagocytosis process (Steinberg et al, 1977). The study of POS ensheathment, separation, and phagocytosis has so far been limited by the low availability of primary human eyes, and hampered our understanding of the molecules that regulate ensheathment and its relationship to phagocytosis
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