The Regulation of Phosphatidylserine Exposure During Photoreceptor Outer Segment Renewal
Abstract
In the mammalian retina, photoreceptor outer segment renewal involves diurnal exposure of phosphatidylserine (PS) at the distal tips of outer segments following light onset. The function of exposed PS serves an “eat-me” signal, stimulating the well-characterized phagocytic machinery of the neighboring retinal pigment epithelium (RPE). However, the regulation of PS exposure following daily light onset remains to be fully understood. Toward this end, I investigated the roles of the extracellular ligand galectin-1 (gal-1), the PS scramblase TMEM16F, and daily light onset itself in regulating PS exposure as part of photoreceptor outer segment renewal.My results revealed that recombinant gal-1 promotes PS exposure at outer segment tips within minutes. While PS tip density may be increased indiscriminately to wild-type peak levels, elongation of individual PS tips is possible only once following light onset in wild-type mice. Furthermore, there is a maximum threshold in PS exposure, equivalent to wild-type peak values, beyond which recombinant gal-1 does not promote in all models tested to date. Moreover, both PS exposure and RPE phagocytosis are altered in mice lacking the PS scramblase TMEM16F (tmem16f-/-), demonstrating that TMEM16F promotes both diurnal PS exposure and RPE phagocytosis. Recombinant gal-1 promotes PS tip density but not length in tmem16f-/- mice, suggesting TMEM16F functions specifically in PS tip elongation promoted by gal-1. This is the first evidence to my knowledge of a role for a phospholipid scramblase in outer segment renewal.Furthermore, the acute absence of light onset impairs both diurnal PS exposure and RPE phagocytosis. Optic nerve manipulations in situ and tissue dissections ex vivo demonstrate light-induced PS exposure is locally controlled. RPE is required for local light regulation, demonstrated by elongation of PS tips following illumination of intact isolated eyecups but not isolated neural retina. Light-induced PS exposure in intact eyecups is prevented by acute inhibition of the photopigment melanopsin. Together, my results provide new insights into the regulation of photoreceptor outer segment renewal. My findings demonstrate critical roles for gal-1, TMEM16F, and daily light onset itself in diurnal PS exposure by outer segment tips and photoreceptor outer segment renewal as a whole.
Subject Area
Cellular biology|Molecular biology|Biology|Ophthalmology
Recommended Citation
Vargas, Jade Ann, "The Regulation of Phosphatidylserine Exposure During Photoreceptor Outer Segment Renewal" (2024). ETD Collection for Fordham University. AAI30989386.
https://research.library.fordham.edu/dissertations/AAI30989386
