Photoreceptor-Pigment Epithelial Cell Relationships in Rats With Inherited Retinal Degeneration

Abstract

Protein synthesis and displacement in photoreceptor and pigment epithelial cells of inbred normal (Fisher) and mutant (RCS) rats with inherited retinal degeneration has been studied by light and electron microscope radioautography . Groups of animals 14, 15,17,19,27, 35, and 50 days of age were injected with amino acids-H 3 and killed at subsequent time intervals . In normal rats, radioactive protein synthesized in the rod inner segments was incorporated into outer segment saccules and displaced outward ; the total renewal time of outer segments at all ages was approximately 9 days . In RCS photoreceptors, outer segment displacement was slowed from the normal rate before day 17 and at all subsequent stages . Most of the newly synthesized protein appeared to migrate only into the basal third of the outer segments . Labeling of pigment epithelial cells in RCS rats was always heavier than in controls. Labeled protein was displaced as early as 1 hr postinjection from pigment epithelial cell somas into the apical processes, and by 2 hr postinjection was located in the adjacent lamellar whorls characteristic of the mutant rat retina . After 1 day, radioactivity was present in the 14, 15, 17, and 19 day series of RCS rats in the apical third of the outer segment layer (occupied mainly by extra lamellar material) while there were few silver grains in the middle third of the layer (occupied mainly by distal parts of outer segments) . The RCS pigment epithelial cells thus have an unusual synthetic role and appear to be a source of the extra lamellar material . Electron microscope examination revealed that many intact pigment epithelial cell processes were incorporated into the large whorls of extra lamellae . In addition, many disorganized outer segment saccules were observed in continuity with longer membranous lamellae and large lamellar whorls . The extra lamellar material therefore appears to be derived from both rod outer segments and pigment epithelial cells .This radioautographic study in rats with in-"These cells which maintain a close relationship herited retinal degeneration explores the relationthroughout life, arise from precursors in adjacent ship between photoreceptor cells and pigment sectors of neuroepithelium in the embryonic epithelial cells at late stages of retinal histogenesis . optic vesicle, and become permanently apposed

Outer Segment Phagocytosis by Cultured Retinal Pigment Epithelial Cells Requires Gas6

“…When phagocytosis becomes dysregulated, as observed in the retinal dystrophic RCS rat, photoreceptors degenerate and blindness progressively ensues (Dowling and Sidman, 1962;Bok and Hall, 1971;LaVail, Sidman and O'Neil, 1972). Consequently the molecular mechanism of OS phagocytosis has been the subject of intense study for many years (reviewed in McLaughlin et al, 1994).…”

Pigment Epithelium-Derived Factor Supports Normal Development of Photoreceptor Neurons and Opsin Expression after Retinal Pigment Epithelium Removal

“…It is well established that the integrity of the photoreceptor outer segment is indispensable for vision to take place and that disorganization of the outer segment is associated with degeneration of that same photoreceptor cell and loss of sight. Indeed, a disruption of photoreceptor outer segments is common to both human (Green et al, 1985;Farber et al, 1987;Rodrigues et al, 1987;Birnbach et al, 1994;Li et al, 1994Li et al, , 1995Milam et al, 1998;Green, 1999) and animal models (LaVail et al, 1972(LaVail et al, , 1975(LaVail et al, , 1982(LaVail et al, , 1985LaVail and Sidman, 1974;LaVail and Mullen, 1976a,b;Edwards and Szamier, 1977;Carter-Dawson et al, 1978;LaVail, 1979;Travis et al, 1989Travis et al, , 1991Narfström et al, 1991;Pittler and Baehr, 1991;Ma et al, 1995;Cheng et al, 1997;Kohl et al, 1998;Kennedy et al, 1999;Redmond et al, 1999) of various types of retinal degenerations. Although the organization of the outer segment is critical, other studies have demonstrated that visual acuity can be preserved despite some loss of photoreceptors.…”

Tyrosine-Mutant AAV8 Delivery of HumanMERTKProvides Long-Term Retinal Preservation in RCS Rats

“…Thinning and atrophy of the RPE begin after the onset of degeneration, and subretinal accumulation of OS debris becomes apparent at P12 to P13. 4,[7][8][9] The retinal vasculature develops normally but begins to show signs of degeneration as early as 3 weeks of age. By 3 to 4 months of age, retinal vessels proliferate abnormally toward the RPE.…”