Development and degeneration of retina in rds mutant mice: Photoreceptor abnormalities in the heterozygotes

doi:10.1016/0014-4835(85)90179-4

Experimental Eye Research

Volume 41, Issue 6, December 1985, Pages 701-720

https://doi.org/10.1016/0014-4835(85)90179-4 Get rights and content

Abstract

Mice homozygous for the rds (retinal degeneration slow) gene fail to develop receptor outer segements and show a slow loss of visual cells that starts from 14–21 postnatal days and results in complete absence at 1 year. In the heterozygous rds/+ mice the development of receptor outer segments is initially retarded. Although a distinct layer of outer segments of moderate length is formed, the disc structures remain disarrayed and form irregular whorls. Autoradiograms of rds/+ retinas show reduced incorporation of [³H]-leucine. Scleral movement of label, resulting from the addition of newly formed discs, is also retarded and appears irregular in comparison with the normal. Phagosomes, containing newly shed disc structures, within the retinal pigment epithelium of rds/+ mice are much larger than normal. Counts taken at different times of the dark- and light periods have shown an abnormally high turnover of phagosomes in the pigment epithelium of the rds/+ mice, with higher than normal peak frequency near the end of the light period, in contrast with the peak frequency in the normal pigment epithelium recorded around the beginning of the light period. Starting at 2 months, a very slow loss of visual cells, much slower than in the homozygous mutants, progresses throughout life. As a result, the outer nuclear layer at the age of 18 months or more is reduced to less than half. Prior to the reduction of the outer nuclear layer, the relative frequencies of the rod and cone perikarya in the rds/+ retina are similar to the normal values. With loss of visual cells, a small increase in the relative frequency of the cone perikarya is recorded in older rds/+ mice. This increase is more noticeable in the central than in the peripheral retina. The significance of the partial expression of the rds gene in the retina of the heterozygous mice in comparison with the changes observed in the homozygous retina is discussed. It is concluded that dose-dependent variation in phenotypic expression is an essential feature in the working of the rds gene.

References (33)

J.G. Hollyfield et al.
The effect of light on the quantity of phagosomes in the pigment epithelium
Exp. Eye Res.
(1976)
T. Kuwabara
Retinal recovery from exposure to light
Am. J. Opthalmol.
(1970)
M.M. LaVail
Rod outer segment disc shedding in relation to cyclic lighting
Exp. Eye Res.
(1976)
S. Sanyal et al.
Absence of receptor outer segments in the retina of rds mutant mice
Neurosci. Lett.
(1981)
A.R. Spurr
A low-viscosity epoxy resin embedding medium for electron microscopy
J. Ultrastruct. Res.
(1969)
R.W. Young
Passage of newly formed protein through the connecting cilium of retinal rods in the frog
J. Ultrastruct. Res.
(1968)
R.W. Young
Shedding of discs from outer segments in the rhesus monkey
J. Ultrastruct. Res.
(1971)
G. Aguirre et al.
Pathogenesis of progressive rod-cone degeneration in miniature poodles
Invest. Ophthalmol. Vis. Sci.
(1982)
S. Basinger et al.
Photoreceptor shedding is initiated by light in the frog retina
Science
(1976)
J.C. Besharse et al.
Turnover of mouse photoreceptor outer segments in constant light and darkness
Invest. Ophthalmol.
(1979)

L.D. Carter-Dawson et al.

Rods and cones in the mouse retina 1. Structural analysis using light and electron microscopy

J. Comp. Neurol.

(1979)

A.I. Cohen

Some cytological and initial biochemical observations on photoreceptors in retinas of rds mice

Invest. Ophthalmol. Vis. Sci.

(1983)

A.I. Goldman et al.

The role of ambient lighting in circadian disc shedding in the rod outer segment of the rat retina

Invest. Ophthalmol. Vis. Sci.

(1980)

A. Grignolo et al.

Retinal damage by visible light in albino rats. An electron microscopic study

Ophthalmologica

(1969)

H.G. Jansen et al.

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

J. Comp. Neurol.

(1984)

R.E. Kirk

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Citation Excerpt :
The size and shape of these phagosomes appeared to be very similar to the abnormal whorled OS structures observed in the rds+/- OS layer (Hawkins et al., 1985). It was proposed that OS structural defects resulted in the RPE consuming larger parts of the OS than normal which took longer to degrade and that this, combined with uptake throughout the day, led to abnormal build-up of phagosomes (Hawkins et al., 1985; Sanyal and Hawkins, 1988). It has never been clearly determined how much of this phenotype was due to structural changes in rds+/- OSs as opposed to defective regulation of the signaling supporting phagocytosis, however work that investigated changes in phagosome numbers in response to light suggested that both factors likely play a role (Sanyal and Hawkins, 1988, 1989).
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Development and degeneration of retina in rds mutant mice: Photoreceptor abnormalities in the heterozygotes

Abstract

Exp. Eye Res.

Am. J. Opthalmol.

Exp. Eye Res.

Neurosci. Lett.

J. Ultrastruct. Res.

J. Ultrastruct. Res.

J. Ultrastruct. Res.

Pathogenesis of progressive rod-cone degeneration in miniature poodles

Invest. Ophthalmol. Vis. Sci.

Photoreceptor shedding is initiated by light in the frog retina

Science

Turnover of mouse photoreceptor outer segments in constant light and darkness

Invest. Ophthalmol.

Rods and cones in the mouse retina 1. Structural analysis using light and electron microscopy

J. Comp. Neurol.

Some cytological and initial biochemical observations on photoreceptors in retinas of rds mice

Invest. Ophthalmol. Vis. Sci.

The role of ambient lighting in circadian disc shedding in the rod outer segment of the rat retina

Invest. Ophthalmol. Vis. Sci.

Retinal damage by visible light in albino rats. An electron microscopic study

Ophthalmologica

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

J. Comp. Neurol.