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The Journal of Neuroscience, June 1, 1998, 18(11):4076-4082
Non-Cell-Autonomous Photoreceptor Degeneration in rds
Mutant Mice Mosaic for Expression of a Rescue Transgene
Wojciech
Kedzierski1,
Dean
Bok2, and
Gabriel H.
Travis1
1 Department of Psychiatry and Program in Neuroscience,
University of Texas Southwestern Medical Center, Dallas, Texas
75235-9111, and 2 Department of Neurobiology, Jules Stein
Eye Institute and Brain Research Institute, University of California
Los Angeles School of Medicine, Los Angeles, California 90095
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ABSTRACT |
The inherited retinal dystrophies represent a large and
heterogenous group of hereditary neurodegenerations, for many of which, the molecular defect has been defined. However, the mechanism of cell
death has not been determined for any form of retinal degeneration. The
retinal degeneration slow (rds /)
mutation of mice is associated with nondevelopment of photoreceptor
outer segments and gradual death of photoreceptor cell bodies,
attributed to the absence of the outer segment protein rds/peripherin.
Here, we examined the effects of a transgene encoding normal
rds/peripherin that had integrated into the X-chromosome in male and
female rds/ mutant retinas. In 2-month-old
transgenic males and homozygous-transgenic females on
rds/, we observed virtually complete rescue of both the outer segment nondevelopment and photoreceptor degeneration. In
contrast, hemizygous-transgenic rds/ female
littermates showed patchy distributions of the transgene mRNA, by
in situ hybridization analysis, and of photoreceptor
cells that contain outer segments. This pattern is consistent with
random inactivation of the X-chromosome and mosaic expression of the
transgene. Surprisingly, we observed significant photoreceptor cell
loss in both transgene-expressing and nonexpressing patches in
hemizygous female retinas. These observations were supported by
nuclease protection analysis, which showed notably lower than predicted
levels of transgene mRNA in retinas from hemizygous females compared
with male and homozygous female littermates. This phenotype suggests an
important component of non-cell-autonomous photoreceptor death in
rds/ mutant mice. These results have significance to
both the etiology and potential treatment of human inherited retinal
degenerations.
Key words:
retinal degeneration; retinitis pigmentosa; rds; peripherin; X-chromosome; cell autonomous; transgene
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INTRODUCTION |
The mammalian retinal dystrophies
represent a large and heterogenous subset of inherited
neurodegenerations. The genetic defect for several retinal
degenerations has been defined (for review, see Travis, 1998 ). In mice
homozygous for the retinal degeneration slow
(rds/) mutation, photoreceptor outer segments completely fail to develop (van Nie et al., 1978; Sanyal et al., 1980; Cohen, 1983). This is followed by death of the rod and cone cell bodies. The
rds gene has been cloned (Travis et al., 1989), and has been shown to encode an integral membrane glycoprotein in outer segment disks named rds/peripherin (Connell et al., 1991; Travis et al., 1991).
The function of rds/peripherin has not been firmly established, but
indirect evidence suggests that it serves as an adhesion molecule to
stabilize the rims of outer segment disks through homophilic and/or
heterophilic interactions across the intradiscal space (Travis et al.,
1991; Bascom et al., 1992; Goldberg et al., 1995; Goldberg and Molday,
1996; Kedzierski et al., 1996). The spontaneous rds mutation
in mice results from the insertion of a repetitive genomic element into
protein-coding exon II (Ma et al., 1995). Although the mutant gene is
transcribed at normal levels in rds/ mutants, no
translation product can be detected (Travis et al., 1991).
rds appears to be a null allele in mice (Travis et al., 1992). In humans, mutations in the RDS gene are responsible
for several inherited retinal dystrophies including retinitis
pigmentosa (RP) (for review, see Keen and Inglehearn, 1996; Shastry,
1997).
Several years ago, we reported complete rescue of the
rds/ mutant phenotype in two transgenic mouse lines that
expressed normal rds/peripherin in rod photoreceptors (Travis et al.,
1992). Subsequent genetic analysis suggested that in line 113, the
rescue transgene had integrated into the X-chromosome. Inactivation of one X-chromosome occurs randomly in cells of female animals during embryogenesis (Monk and Grant, 1990; Kay et al., 1994; Moore et al.,
1995). Retinas from hemizygous line 113-transgenic females (transgene
present on only one X-chromosome) should therefore be mosaic for
expression of the transgene. Photoreceptors derived from precursor
cells in which the transgene-containing X-chromosome was inactivated
are predicted to manifest the full rds/ phenotype, with
absent outer segments and death of the cell bodies. Photoreceptors derived from precursor cells in which the transgene-containing X-chromosome is transcriptionally active should be normal. The latter
case prevails with all photoreceptors in 113-transgenic males and in
homozygous-transgenic females (transgene on both X-chromosomes). Here,
we report the phenotype of hemizygous-transgenic female mice on an
rds/ mutant background. As predicted, we observed a
mosaic pattern of transgene-expression by in situ
hybridization analysis, and the patchy distribution of photoreceptor
outer segments. Unexpectedly, significant photoreceptor cell loss was
observed in the transgene-expressing patches of retinas from
rds/ hemizygous females, despite virtually complete
protection of these cells from degeneration in homozygous female and
male littermates.
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MATERIALS AND METHODS |
Analysis of transgenic mice. Mice of wild-type
rds-transgenic line 113 were generated as described (Travis
et al., 1992). The transgenic status and genetic background at
rds were determined by PCR (Kedzierski et al., 1997).
Homozygous and hemizygous transgenic females were distinguished by
comparative PCR (Chatelain et al., 1995). All animals were tested twice
using two independent tail DNA preparations, and only those of
unambiguous genotype were used in further studies. In all experiments,
mice were killed at 4-6 hr after light onset (12 hr light/dark
cycles).
In situ hybridization. Eyecups dissected from mice were
placed in PBS, and whole retinas were collected and fixed in PBS
containing 4% paraformaldehyde overnight at 4°C. In situ
hybridization was performed according to the protocol of Riddle et al.
(1993) and modified by Bruhn and Cepko (1996). For the probe,
digoxigenin-labeled antisense RNA was synthesized from a linearized
plasmid template containing a 900 bp SV40 fragment of the transgene
construct (Fig. 1A),
using T7 RNA polymerase. After overnight hybridization, signals were
detected with a digoxigenin nucleic acid detection kit (Boehringer Mannheim, Indianapolis, IN), following the manufacturer's protocol. For tissue section figures, flat-mount retinas were frozen in OCT
(Miles Incorporated, Kankakee, IL) after hybridization, and 10 µm
sections were cut, thawed onto glass slides, and photographed.
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Figure 1.
Line 113 wild-type rds transgene.
A, Map of transgene construct; 6.5 kb from upstream of
mouse rhodopsin gene, including 80-bp from the 5'-untranslated region,
is fused to a wild-type rds cDNA fragment containing the
complete protein-coding region. The site of transcriptional initiation
is indicated by a bent arrow. The SV40 t-intron and
polyadenylation signal function as a transcriptional terminator.
Heavy bars show regions represented by riboprobes for
nuclease protection (a), and in
situ hybridization analysis (b).
B, Pedigree showing eight generations of line 113. Squares, Males; circles, females;
solid figures, transgenic; open figures,
nontransgenic mice.
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Nuclease protection analysis. Total RNA was extracted from
individual eyecups using Tri Reagent (Molecular Research Center, Cincinnati, OH), according to the manufacturer's protocol, and hybridized with a 32P-labeled antisense RNA probe of 280 nucleotides (nt), derived from the transgene construct (Fig.
1A, fragment a). After S1-nuclease digestion, protected fragments were analyzed by electrophoresis on an
8% polyacrylamide gel containing 8 M urea. Each lane
contained total RNA from a single mouse retina. The probe protected a
169 nt fragment corresponding to the endogenous rds mRNA,
and a 209 nt fragment corresponding to the transgenic mRNA (Kedzierski
et al., 1997). To quantitate the protected fragments, a standard curve
was prepared using in vitro-transcribed sense rds
RNA. Known amounts of this RNA standard were subjected to the same
treatment as total RNA. Radioactive bands corresponding to the
protected fragments were quantitated on a model 425F PhosphorImager
(Molecular Dynamics, Sunnyvale, CA) and compared with RNA standards on
the same gel. We corrected for differences in nucleotide composition and protected fragment length in determining the absolute level of each
mRNA per retina.
Light and electron microscopy. Mice were anesthetized with
50 mg/kg Nembutal (Abbott Laboratories, Santa Clara, CA) and
subsequently fixed by transcardiac perfusion with formaldehyde and
glutaraldehyde (1 and 2%, respectively) in 0.1 M sodium
phosphate buffer, pH 7.2. After the eyes were dissected, the posterior
portion of each eye was cut into quadrants and fixed additionally for 1 hr with 1% osmium tetroxide in 0.1 M sodium phosphate
buffer, pH 7.2. The tissues were then dehydrated and embedded in
Araldite 502 (Ciba Geigy, Basel, Switzerland). Sections of 0.5 µm
thickness were stained with toluidine blue before light microscopy.
Ultrathin sections for electron microscopy were stained with uranium
and lead salts.
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RESULTS |
The line 113 rds-transgene integrated into
the X-chromosome
The transgenic construct is depicted in Figure
1A. This transgene gives rod-specific expression of a
mRNA encoding normal rds/peripherin at a similar level to that of the
endogenous rds mRNA (Travis et al., 1992). A pedigree
showing several generations of mice from transgenic line 113 is shown
in Figure 1B. Note that males always transmit the
transgene to their female but never their male offspring, whereas
hemizygous females transmit to both male and female offspring. This
pattern of inheritance is only consistent with integration of the
transgene into the X-chromosome.
Mosaic expression of the transgene in retinas from
hemizygous females
We performed in situ hybridization analysis on
whole-mount retinas from 1-month-old mice of different genotypes using
an antisense SV40 riboprobe (Fig. 1A, fragment
b). Uniform labeling was observed across the entire retina
in transgenic male and homozygous-transgenic female mice (Fig.
2B,D). Patchy labeling
was observed in retinas from female hemizygous-transgenic mice
(Fig. 2C). No labeling was observed in retinas from
nontransgenic C57BL/6 mice (Fig. 2A). After
hybridization, the retinas were cut into 10 µm sections. Patchy
labeling was observed in the outer retinal (photoreceptor cell) layer
of hemizygous transgenics, whereas homozygous females showed uniform
labeling of the photoreceptor cell layer (Fig. 2E,F).
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Figure 2.
In situ hybridization analysis of
retinas from 1-month-old mice using a digoxigenin-labeled riboprobe
complementary to SV40 in the transgene. A, Whole mount
of a retina from a nontransgenic C57BL/6 mouse. B, Whole
mount of a retina from a male transgenic mouse on
rds/ genetic background. C, Whole
mount of a retina from a female transgenic hemizygote on
rds/. D, Whole mount of a retina from
a female transgenic homozygote on rds/. Sections
encompassing ~20% of one retinal diameter are represented in plates
A-D. A retinal edge is included in each plate to show
the photographic background intensity. Note the patchy distribution of
hybridization signal in C. E,
Full-thickness section of retina from female transgenic hemizygote on
rds/. F, Full-thickness section of
retina from female transgenic homozygote on rds/.
Note the interrupted hybridization signal in the photoreceptor cell
layer in E compared with F.
Magnification: A-D, 70×; E, F,
120×.
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Expression of endogenous and transgenic rds mRNAs
Nuclease protection analysis was done on individual retinal
samples from mice of different genotypes at 12 d and 2 months using a riboprobe that distinguished the transgenic from the endogenous rds mRNAs (Fig. 3). The
absolute level of each RNA species per retina was determined in six
mice of each genotype (Table 1). We
observed the approximate doubling of RNA levels in mice of comparable
genotypes between 12 d and 2 months, presumably because of retinal
growth and maturation. The level of the transgene mRNA in 12-d-old
female homozygotes on an rds/ background was
approximately equal to that of male transgenic littermates and
approximately twice that of female transgenic hemizygotes. By 2 months,
the level of the transgenic mRNA in female hemizygotes was only 26% that of male littermates, suggesting loss of transgene-expressing photoreceptors in female hemizygotes.
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Figure 3.
Nuclease protection analysis of retinal RNA. An
antisense rds riboprobe (280-nt) was used to protect a
209 nt fragment of the transgene mRNA and a 169 nt fragment of the
wild-type or mutant endogenous rds mRNA.
A, Representative lanes from 12-d-old mice of the
indicated genotypes. Transgenic hemizygotes are indicated by
TG, and homozygote is indicated by TG/TG.
B, Representative lanes from 2-month-old mice of the
indicated genotypes. A series of five quantitation standards containing
from 400 to 6400 attomoles of RNA are shown to the right
of each gel.
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Numbers of photoreceptors are similar in young transgenic male and
hemizygous transgenic female mice
We examined retinas from 12-d-old transgenic male and
hemizygous-transgenic female littermates on the rds/
genetic background (Fig. 4). Outer
segments were shorter and less organized than those of transgenic male
littermates. Significantly, outer nuclear layer thickness at 12 d
was identical in hemizygous-transgenic females and transgenic males and
comparable to that of nontransgenic wild-type controls (data not
shown). This result suggests that hemizygous transgenic females begin
with a similar number of photoreceptor cells as their male
counterparts.
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Figure 4.
Light micrographs of retinal sections from
predegenerate transgenic mice. A, Retina from 12-d-old
transgenic male on rds/ background.
B, Retina from 12-d-old hemizygous-transgenic female on
rds/ background. Note the similar thickness of outer
nuclear layers (ONL) (dark stained nuclei) in both
sections. Magnification, 490×.
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Patchy outer segment dysplasia and photoreceptor degeneration in
hemizygous-transgenic females
By light microscopic analysis, outer nuclear layer thickness and
outer segment appearance were virtually indistinguishable in retinas
from transgenic male and homozygous-transgenic female mice on
rds/ and nontransgenic wild-type mice, all at 2 months of age (Fig. 5A-C). In
contrast, retinas from hemizygous-transgenic female littermates showed
a discontinuous pattern of photoreceptor patches that contain or lacked
outer segments (Fig. 5D). The outer nuclear layer was
uniformly thinner in these females, with five or six rows of
photoreceptor nuclei, suggesting significant photoreceptor degeneration. Retinas from 2-month-old nontransgenic
rds/ mutant mice contained four or five rows of
photoreceptor nuclei with absent outer segments throughout (Fig.
5E). Electron microscopic analysis of retinas from 2 month
hemizygous-transgenic rds/ female mice showed patches of
photoreceptors containing outer segments adjacent to patches of
photoreceptors that completely lack outer segments (Fig.
6). The outer segments were well
organized but somewhat shortened compared with wild type.
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Figure 5.
Light micrographs of retinal sections from
2-month-old mice of several genotypes. A, Nontransgenic
C57BL/6 wild-type. B, Transgenic male on
rds/. C, Homozygous-transgenic female
on rds/. D, Hemizygous-transgenic
female on rds/. E, Nontransgenic male
rds/ mutant. Arrows in D indicate
patches of photoreceptors that lack outer segments. Note the normal
appearance of outer segments (OS) and similar thickness of outer
nuclear layers in A-C. Also note the similar reductions
in outer nuclear layer-thickness in D and
E. Outer segments are completely lacking in
E. Magnification, 490×.
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Figure 6.
Electron micrograph of a distal retina from a
2-month-old hemizygous-transgenic female rds/ mouse.
Shown is a region containing small patches of photoreceptors that
contain and lack outer segments. Photoreceptor inner segments
(IS), outer segments (OS), and retinal
pigment epithelium (RPE) are labeled. Note the absence
of outer segments (OS) in the nonexpressing patches
(large arrows) and the presence of vesicular debris
(small arrows). Magnification, 5500×.
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DISCUSSION |
Based on the results of retroviral tagging studies, the vertebrate
retina is thought to develop from a germinal epithelial layer, in which
individual progenitor cells give rise to all classes of neurons within
a radial column (Turner and Cepko, 1987; Holt et al., 1988;
Fields-Berry et al., 1992). Recently, a line of transgenic mice was
described containing a ubiquitously expressed lacZ reporter
gene that had integrated into the X-chromosome (Reese et al., 1995).
When female retinas from this line were stained with X-gal, a fine
mosaic pattern of radially arranged blue and white columns was
revealed. Virtually no lateral dispersion of blue-stained
photoreceptors into nonstained patches was seen. These observations
suggest that during development, minimal intermingling occurs between
photoreceptors derived from distinct clonal precursor cells.
We observed two morphological patterns of mosaicism in retinas from
line 113 hemizygous-transgenic females on an rds/ mutant background. First, patchy expression of the transgene was seen in
photoreceptors by in situ hybridization. Male and homozygous female littermates, in contrast, showed uniform expression of the
transgene. Second, we observed a patchy distribution of photoreceptors containing outer segments in hemizygous-transgenic female retinas. The
size of these patches varied in width from several cell diameters to
>50. The observed mosaic pattern of transgene expression in these
females is likely attributed to random inactivation of the transgene-bearing X-chromosome. X inactivation has been shown to occur
between 5.5 and 10.5 d after conception in different tissues of
the mouse embryo (Tan et al., 1993). The precise time of X inactivation
in the developing optic vesicle has not been determined. The fine
pattern of retinal mosaicism observed by us and others (Reese et al.,
1995) suggests that X inactivation occurs late within this time window
in retinal precursor cells.
An unexpected finding in the current study was that both
transgene-expressing and nonexpressing photoreceptors undergo
degeneration in hemizygous-transgenic females on the
rds/ genetic background. This conclusion was based on
several observations. If transgene-expressing photoreceptors in
rds/ female retinas were protected from degeneration, as
they are in males and homozygous females, we would have expected outer
nuclear layers of irregular width, with ~10 rows of nuclei in patches
of photoreceptors that contain outer segments, and four or five rows in
non-transgene-expressing patches (Sanyal et al., 1980). Instead, we
observed uniform thinning of outer nuclear layers across
transgene-expressing and nonexpressing patches. Could this observation
be explained by the lateral migration of transgene-expressing
"rescued" photoreceptors into nonexpressing patches? Although some
lateral migration may occur, the number of photoreceptors in
hemizygous-female retinas is significantly fewer than can be accounted
for by this explanation. The outer nuclear layer width in 2-month-old
hemizygous female retinas (five or six rows) was nearly the same as in
nontransgenic rds/ littermates (four or five rows). If
the observed uniformity of outer nuclear layer width was attributed
only to lateral migration of transgene-expressing photoreceptors, we
would have expected an overall thickness of about seven rows in these
females. Furthermore, by nuclease protection analysis, the absolute
level of transgene mRNA in hemizygous female retinas was approximately
half that of both transgenic males and homozygous-transgenic females at
12 d. However, by 2 months, the level of the transgene mRNA in
hemizygous females dropped to approximately one-fourth that of the male
littermates. If transgene-expressing photoreceptors were protected from
cell death in hemizygous females, as they are in males and homozygous
females, we would have expected a female-to-male expression ratio of
~50% at both 12 d and 2 months. Collectively, these data
suggest that the transgene-expressing photoreceptors are dying at a
much higher rate in hemizygous female retinas compared with males and
homozygous females on the same rds/ genetic
background.
We observed accumulations of vesicular debris in the subretinal space
(between photoreceptors and cells of the pigment epithelium) in
nonrescued patches of hemizygous-transgenic female retinas (Fig. 6).
Similar vesicles have been observed in the subretinal space of
nonmosaic rds/ mutant mice (Jansen and Sanyal, 1984). These vesicles react strongly with antibodies against rhodopsin (Nir
and Papermaster, 1986; Jansen et al., 1987; Usukura and Bok, 1987),
suggesting that they are composed of membrane destined to form outer
segments, which failed to form disks because of the absence of
rds/peripherin. These vesicles do not accumulate with age in
rds/ mice, implying that they are cleared by the pigment
epithelium, as are shed outer segments in normal retina. A possible
explanation for the observed accumulation of vesicles in female mosaic
retinas is that neighboring outer segments in transgene-expressing
patches confer a "tent pole" effect, physically separating the
pigment epithelial cells from the photoreceptor ciliary processes, and
thus slowing phagocytosis. Although the organization of outer segments
in the transgene-expressing photoreceptors is normal, these structures
are somewhat shorter than those observed in wild-type retinas or
retinas from transgenic rds/ males. Because addition of
outer segment disks is a continuous process in adult photoreceptors
(Young and Bok, 1969), representing a significant metabolic burden to
the cell, the shortening of outer segments within the
transgene-expressing patches may be an early sign of reduced
photoreceptor viability.
A possible explanation for the death of transgene-expressing cells is
that degenerating photoreceptors release a toxic factor or factors that
trigger apoptosis in neighboring cells. In rds/ mutants,
40% of photoreceptors are lost during the first month (Nir et al.,
1990). This is followed by more gradual loss of the remaining
photoreceptors over months to years, depending on the background strain
(Sanyal et al., 1980). This rapid phase of degeneration may reflect a
positive feedback between the cell-autonomous and nonautonomous
effects, resulting in accelerated release of toxic factors by the dying
cells. Cells "left standing" after the initial devastation may die
more slowly because of reduced generation of these toxic factors.
Several other observations support this model. Sanyal and Zeilmaker,
(1984) described retinal morphologies in wild-type  rds/ aggregation chimeras. Although quantitative analysis of retinal degeneration was not done in these mice, a reduction in the number of photoreceptor nuclei to a level intermediate between that of wild-type and rds/ mutant retinas was
observed. Also, aggregation chimeras were generated between wild-type
and transgenic mice carrying the dominant RP-associated P347S mutation in a pig rhodopsin gene (Huang et al., 1993). Here, the authors observed uniform reductions in the number of photoreceptor nuclei across both transgenic and nontransgenic patches, again suggesting a
non-cell-autonomous mechanism of photoreceptor death.
An alternative explanation for non-cell-autonomous photoreceptor loss
is that viable photoreceptors confer a trophic effect on one another.
In the wild-type P347S chimeras reported by Huang et al. (1993),
the rate of photoreceptor cell loss was correlated with degree of
transgenic chimerism. As the authors proposed, this result suggests a
protective effect of wild-type cells on cells expressing the mutant
transgene. Thus, non-cell-autonomous photoreceptor death in hemizygous
females may be attributable, at least in part, to loss of a trophic
effect required for photoreceptor survival.
Humans are affected by a heterogenous group of inherited retinal
degenerations, typified by RP. Multiple genes have been implicated in
RP, most of which are expressed specifically in rod but not cone
photoreceptors (for review, see Travis, 1998). However, RP is
invariably associated with the death of both rod and cone photoreceptor cells (Heckenlively, 1988). Cone cell degeneration in RP caused by
mutations in rod-specific genes may represent still another instance of
non-cell-autonomous photoreceptor death. Finally, in X-linked RP, a
significant fraction of human female "carriers" are reported to
have visual abnormalities (Bird, 1975; Rusin et al., 1989; Friedrich et
al., 1993; Stavrou et al., 1996). By definition, these carriers are
mosaic for expression of the mutant X-linked RP allele. The mechanism
of visual loss in X-linked RP carriers has never been defined. This
disease process may be similar to what we observe in retinas from
hemizygous-transgenic female rds/ mutants. Thus, in
several disparate systems, photoreceptor degeneration appears to be
mediated by a combination of cell-autonomous and non-cell-autonomous
effects. A common cellular process may underlie these different
examples of photoreceptor degeneration.
In summary, we have characterized the effects on retina of a wild-type
rds transgene that integrated into the X-chromosome. When
placed on an rds/ genetic background, this transgene
resulted in mosaic rescue of the outer segment phenotype in hemizygous females. Significant photoreceptor cell loss was observed in both transgene-expressing and nonexpressing retinal patches. This
observation suggests the existence of a major non-cell-autonomous
component to photoreceptor degeneration in rds/ mutants.
A similar process may be operative in other mammalian retinal
degenerations, including RP in humans. It may also explain the high
prevalence of visual abnormalities in female carriers of X-linked RP.
Finally, because photoreceptors are a subtype of neurons,
non-cell-autonomous degeneration may occur in other neurodegenerative
disorders, including those not involving inflammation. If true, this
has important therapeutic ramifications. Identifying the putative
extracellular signal(s) that trigger apoptosis in neighboring neurons
could lead to the development of pharmaceutical agents that may slow
progression of these diseases. The line 113 transgenic mouse would be a
useful animal model to test the efficacy of these potential treatments on the non-cell-autonomous component of neuronal degeneration.
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FOOTNOTES |
Received Feb. 20, 1998; accepted March 20, 1998.
This work was supported by grants from the National Eye Institute and
the Foundation Fighting Blindness. D.B. is the Dolly Green Professor of
Ophthalmology and a Research to Prevent Blindness Senior Scientific
Investigator. We gratefully acknowledge the excellent technical
assistance of Marcia Lloyd, Roxana Radu, and Zifen Wang. We thank
Sassan Azarian, Nathan Mata, and Izhak Nir for their valuable comments
on this manuscript.
Correspondence should be addressed to Gabriel H. Travis, University of
Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas,
TX 75235-9111.
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Abstract
Introduction
