Development and degeneration of retina in rds mutant mice: Light microscopy

Abstract

Changes during the development and degeneration of the retina in 020/A mice, which are homozygous for the newly reported rds (retinal degeneration slow), gene were studied by histological and enzyme-histochemical methods with Balb/c mice carrying the normal allele as control. During normal development the total thickness of the retina grows from the time of birth till the age of 21 days and thereafter gradually diminishes, while the thicknesses of the component layers show a characteristic and differential change in course of their histogenesis. In the normal retina the perikarya of the cones are more frequent in the central than in the peripheral areas. The cone frequency in the central retina, but not in the periphery, increases with age and implies selective loss of rod cells in older animals. In the homozygous rds mice, the receptor layer remains rudimentary, but the other retinal layers show a normal trend of growth during the first 2 weeks after birth. Thereafter th morphological layers containing visual cell structures--the receptor, the outer nuclear, and the outer plexiform layers--begin to reduce. The loss of visual cells is readily marked by the reduction of the outer nuclear layer and is first evident at 2 weeks after birth. Degeneration is more rapid up to the age of 2-3 months, when the outer nuclear layer is reduced to half of its original thickness; thereafter degeneration progresses more slowly. The receptor and the outer plexiform layers are also simultaneously reduced. At 9 months, the peripheral parts of the retina, and at 12 months, the entire retina is completely lacking in visual cells. In the central retina of the mutant, rod and cone cell populations are equally affected up to the age of 6 months, as their relative frequency remains similar to the normal. In the peripheral retina, where cell loss is more pronounced, and in the central retina at 9 months an increase in relative frequency of cones is recorded and indicate increased susceptibility of the rods to later degenerative changes. The inner parts of the retina, including inner nuclear, inner plexiform, and ganglion cell layers, remain morphologically unaffected until irregular vascularization follows total loss of visual cells. The pigment epithelium is also affected at this late stage and appears depleted and patchy. In the normal retina, macrophages which are positively stained for the enzyme N-acetyl-beta-glucosaminidase appear in the inner layers with the growth of the retinal vasculature. In the mutant, increased frequency and stainability of the macrophages are discernible in the inner retina at 11 days. The macrophages migrate outwards and are observed in the outer nuclear layer and in the optic ventricle during the period of degeneration. These findings are compared with the observations in the other retinal degeneration mutants in rodents, and in retinitis pigmentosa in humans. The suitability of the rds mice as an animal model system for the human disease is emphasized.

Morphological characterization of the retinal degeneration in three strains of mice carrying the rd-3 mutation

“…Such patterns of hypopigmentation, due to a variety of causes including but not limited to RPE cell dropout, have been seen in fundus photographs of most of the known murine inherited retinal degenerations~Hawes et al, 1999;Chang et al, 2002;Mehalow et al, 2003;Pang et al, 2005!. As we have reported here, several studies correlate areas of RPE cell thinning with the apposing and localized loss of photoreceptor cell bodies comprising the ONL~Caley et al, 1972;Sanyal & Bal, 1973;Sanyal et al, 1980;LaVail et al, 1982LaVail et al, , 1993Blanks et al, 1982;Messer et al, 1993!. As in other photoreceptor degenerations, Müller cells fill in space left by these dying photoreceptors. Though immunocytochemistry shows that there is some upregulation of GFAP in these cells, as has been seen in other retinal degenerations~Eisenfeld et al, 1984;Lewis et al, 1994!, we , there is an increase in apoptotic profiles though they are still restricted to the inner retinal layers.…”

“…data showed a strong correlation between the time course of photoreceptor loss in each strain and the gradual extinction of the a-wave in each~Chang et al, 1993a; Heckenlively et al, 1993b; Nusinowitz et al, 1997!. These results indicated that the time course of the rd-3 rod0cone degeneration is of intermediate duration when compared to other retinal degenerations in micẽ Carter-Dawson et al, 1978;Messer et al, 1993;Mullen & LaVail, 1975;Sanyal et al, 1980!. Photoreceptor degeneration begins at the time of outer segment differentiation, reaching completion in 2-4 months.…”

Retinal Degeneration Slow (RDS) Glycosylation Plays a Role in Cone Function and in the Regulation of RDS·ROM-1 Protein Complex Formation

“…The RDS/PRPH2 gene codes for a photoreceptor-specific glycoprotein called retinal degeneration slow (RDS 2 or peripherin-2), which is a member of the tetraspanin family of proteins and is critical for the proper formation of both rod and cone photoreceptor outer segments (OSs) (1)(2)(3)(4)(5)(6)(7)(8). The OS is an organelle comprising a series of flattened opsin-packed discs and is specialized to detect incoming light and initiate phototransduction (9 -11).…”

“…Over 80 individual mutations of the RDS/PRPH2 gene in humans have been associated with significant diseases of the retina that can range from the rod-dominant retinitis pigmentosa to the cone-dominant diseases cone-rod dystrophy and macular degeneration (12). Additionally, extensive studies in mouse models have clearly demonstrated the importance of the RDS protein to retinal structure and function (2,(13)(14)(15)(16)(17)(18). In mice heterozygous for the Rds gene (rds ϩ/Ϫ ), the OSs become highly disorganized, and the discs adopt a bizarre whorl-like morphology.…”

N-Methyl-N-nitrosourea-induced Retinal Degeneration in Animals

“…At 72 hr after MNU treatment, detachment of the pigment epithelial cells from Bruch's membrane was seen, and, at day 7, 21 and 35, migrating pigment-containing cells were present in all layers of the retina. In agreement to inherited retinal degeneration mice [5,47], Müller cells, macrophages and migrated pigment epithelial cells are involved in removal of apoptotic cells. However, the migrated melanincontaining cells were not in contact with blood vessels.…”