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The Journal of Neuroscience, March 15, 2000, 20(6):2150-2154
Expression of Bcl-2 Protects against Photoreceptor Degeneration
in retinal degeneration slow (rds) Mice
Izhak
Nir1,
Wojciech
Kedzierski2,
Jeannie
Chen3, and
Gabriel H.
Travis2
1 Department of Pharmacology, University of Texas
Health Science Center, San Antonio, Texas 78284, 2 Center
for Basic Neuroscience and Department of Psychiatry, University of
Texas Southwestern Medical Center, Dallas, Texas 75235, and
3 Mary D. Allen Laboratory for Vision Research, Doheny Eye
Institute, Departments of Ophthalmology and of Cell and Neurobiology,
Keck School of Medicine at the University of Southern California, Los
Angeles, California 90033
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ABSTRACT |
The retinal degeneration slow or rds
gene encodes rds/peripherin, an integral membrane glycoprotein in the
outer segments of rod and cone photoreceptors. Mice homozygous for a
null mutation in rds fail to develop outer segments and
undergo subsequent degeneration of photoreceptors by the apoptotic
pathway. Mutations in the human RDS gene are responsible
for several forms of inherited blindness including autosomal-dominant
retinitis pigmentosa and macular degeneration. Here, we examined the
effects of ectopic Bcl-2 expression in transgenic photoreceptors on the
rate of retinal degeneration in rds mutant mice. We
observed an approximately twofold preservation of photoreceptors
compared with nontransgenic rds mutant mice at 3 months.
Immunoblot analysis showed similar levels of Bcl-2 in 2-, 3-, and
4-week-old transgenic mice. Expression of Bcl-2 in the
rds mouse did not lead to outer segment formation and
did not induce cell death. These results suggest that Bcl-2 expression may be an effective therapeutic strategy in humans with mutations in
RDS or other genes that affect the integrity of
photoreceptor outer segments.
Key words:
rds mice; rds/peripherin; retinal
degeneration; retinitis pigmentosa; Bcl-2; transgene; apoptosis
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INTRODUCTION |
The mammalian retina is a useful
system for studying neuronal degeneration. Mutations in multiple genes
have been shown to cause blindness because of photoreceptor cell death
(for review, see Molday, 1998 ; Travis, 1998). An example is the retinal
degeneration slow or rds mouse. Photoreceptors in mice
homozygous for a null mutation in the rds gene fail to
develop outer segments, the site of photon capture and of the reactions
of visual transduction (Jansen and Sanyal, 1984). Photoreceptor cell
death starts between the second and third postnatal week and is
completed at ~1 year (Sanyal et al., 1980; Nir et al., 1990). A light
response can be elicited in rds mice although at a greatly
reduced sensitivity (Reuter and Sanyal, 1984). The residual
photoactivity is mediated by opsin that is localized in the inner
segment and connecting cilium plasma membranes (Nir and Papermaster,
1986).
In humans, over 50 mutations in the RDS gene have been
implicated in dominant forms of retinitis pigmentosa (RP) and macular degeneration (for review, see Keen and Inglehearn, 1996; Shastry, 1997). RDS encodes rds/peripherin, a structural glycoprotein
in the rims of outer segment disks (Connell et al., 1991; Travis et
al., 1991; Kedzierski et al., 1999). In previous studies, we demonstrated complete rescue of the rds phenotype in
transgenic mice that express normal rds/peripherin (Travis et al.,
1992). Subsequently, we showed that the rds rescue transgene
integrated into chromosome X in line 113 mice. Hemizygous females from
line 113 showed mosaic expression of the transgene and partial rescue of the rds phenotype, whereas males of this line were
completely rescued (Kedzierski et al., 1998).
The events that lead from primary mutation to the onset of cell death
are not known for any form of retinal degeneration. In every system
studied, however, photoreceptors have been shown to die by the
apoptotic pathway (Chang et al., 1993; Lolley et al., 1994;
Portera-Cailliau et al., 1994; Tso et al., 1994; Cook et al., 1995;
Abler et al., 1996; Molthagen et al., 1996). An important step in
apoptosis is the release of cytochrome c from the intermembrane space
of mitochondria (Krippner et al., 1996; Li et al., 1997). Members of
the Bcl-2 protein family exert antiapoptotic effects by blocking the
release of cytochrome c from mitochondria (Kluck et al., 1997; Yang et
al., 1997). Bcl-2 is not expressed in mature photoreceptors, although
the related protein Bcl-XL is present in these
cells (Levin et al., 1997).
Prevention of photoreceptor death by ectopic expression of Bcl-2 was
attempted in several mouse models of inherited retinal degeneration.
These studies showed either no effect (Joseph and Li, 1996) or
limited and short-lived effects (Chen et al., 1996; Tsang et al.,
1997). In the current study we examined the effects of Bcl-2 expression
on photoreceptor death in rds mutant mice that undergo a
relatively slow degeneration, similar to many forms of retinal
degenerations in humans. We show that expression of Bcl-2 causes a
significant and long-term suppression of photoreceptor cell death in
homozygous rds mutants.
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MATERIALS AND METHODS |
Transgenic mice. Mice carrying a transgene (line B)
containing the complete human Bcl-2-coding region downstream of a mouse rhodopsin promoter (Chen et al., 1996) were crossed onto an
rds / homozygous mutant background on the C57BL/6 strain.
The resulting F1 mice were crossed with rds line
113-transgenic mice, also on an rds/ background, to
yield F2 progeny of the desired genotypes. Mice were maintained under a
12 hr dark/light cycle at 40 lux illumination. Tail-cut DNA from mice
was analyzed for the presence of the rds transgene by PCR
with the following primers: 5'-CCTGGAGTTGCGCTGT and
5'-GTCTTTTT- CATGAAGCACC from the mouse rhodopsin promoter and the
rds-coding region, respectively (Travis et al., 1989). Mice
were analyzed for the presence of the Bcl-2 transgene by PCR with the
following primers: 5'-CCTGGAGTTGCGCTGT and 5'-CCTGTTCTCCCAGCGT from the
mouse rhodopsin promoter and the human Bcl-2-coding region, respectively.
Microscopy. Mice were killed by cervical dislocation; the
eyes were enucleated and placed in 4% formaldehyde and 2%
glutaraldehyde in 0.1 M phosphate buffer for fixation.
After 30 min, the eyes were bisected along the vertical meridian. The
two hemispheres were fixed for an additional 3 hr. The tissue was then
treated in 1% OsO4, embedded in araldite. One
micrometer sections were prepared for analysis of the outer nuclear
layer (ONL) thickness by light microscopy. Thin sections from the same
regions of the retina were used for ultrastructural analysis.
Measurement of photoreceptor survival. Light microscopy was
used for quantitative assessments of photoreceptor survival. Sections of 1 µm thickness were cut along the superior-inferior meridian. Each section included the full retina from optic nerve head to ora
serrata. The number of photoreceptor nuclei within the ONL was counted
along the posterior-periphery axis at a distance of 150-1500 µm
from the optic nerve head in the superior and inferior hemispheres.
Measurements were performed at 150 µm intervals using an eyepiece
graticule. Data are expressed as the number of photoreceptor nuclei in
a 50 µm retinal length.
Immunoblot analysis of human Bcl-2. Dissected mice retinas
were homogenized on ice in 10 mM Tris-HCl, pH 7.5, 1% SDS,
1 mM EDTA, 0.2 mM phenylmethylsulfonyl
fluoride, and protease inhibitor cocktail (Boehringer Mannheim,
Indianapolis, IN) and cleared by a 2 min centrifugation in a microfuge
at 4°C. The extracts were mixed with 2× Laemmli buffer and incubated
at 65°C for 2 min. Samples were resolved by 10% PAGE in 10%
0.75 mm gels and electrotransferred to Immobilon P membranes
(Millipore, Bedford, MA) in a transfer buffer containing 25 mM Tris-HCl, 190 mM glycine, 15% methanol, and
0.05% SDS. Blots were preblocked for 1 hr by treating with 1% nonfat
dry milk in PBS. The blots were incubated for 2 hr with a mouse
monoclonal antibody against human Bcl-2 (Sigma, St. Louis, MO) diluted
1:1000 with PBS containing 1% dry milk. After being washed with
PBS containing 0.05% Tween 20 for 1 hr, blots were incubated for an
additional hour with goat anti-mouse IgG-horseradish peroxidase
conjugate (Bio-Rad, Richmond, CA) diluted 1:10,000 with PBS containing
1% dry milk. Blots were detected with the LumiGLO chemiluminescent
substrate (Kirkegaard & Perry, Gaithersburg, MD).
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RESULTS |
Photoreceptor survival in 3-month-old retinas
We studied photoreceptor survival by light microscopy in
3-month-old mice of the following genotypes: (1) nontransgenic
rds/ homozygotes (rds), (2) Bcl-2-transgenic,
rds/ homozygotes (rds:bcl), (3) rds
rescue transgenic, rds/ homozygotes
(rds:113), and (4) Bcl-2 and rds rescue double-transgenic,
rds/ homozygotes (rds:113+bcl). Representative retinal sections from males of these four genotypes are
shown in Figure 1. Nontransgenic
rds mice showed significant retinal degeneration at 3 months, with reductions in ONL thickness to two to three rows of nuclei
(Fig. 1A). Expression of Bcl-2 in rds:bcl
mice resulted in a partial rescue of retinal degeneration, with
retention of five to six rows (Fig. 1B). Expression
of normal rds/peripherin in male rds:113 mice prevented
retinal degeneration, with retention of eight to nine rows of nuclei
(Fig. 1C). Expression of both rds/peripherin and Bcl-2 in
rds:113+bcl mice also resulted in full protection from
retinal degeneration, with retention of eight to nine rows of nuclei
(Fig. 1D).
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Figure 1.
Light micrographs of retinal sections from
3-month-old male mice of different genotypes. The densely stained
photoreceptor nuclei layer is indicated in each panel by
a white vertical bar. A, Homozygous
rds retina (rds). Up to three rows of
photoreceptor nuclei are present. B, Homozygous
rds retina expressing the Bcl-2 transgene
(rds:bcl). Up to six rows of nuclei are present.
C, Homozygous rds retina expressing the
normal rds/peripherin transgene (rds:113). Up to eight
rows of nuclei are present. D, Homozygous
rds retina expressing the normal rds/peripherin plus
Bcl-2 transgenes (rds:113+bcl). Up to eight rows
of nuclei are present. ris, Rod inner segment layer;
ros, rod outer segment layer. Magnification,
400×.
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We performed detailed morphometric analysis to define accurately the
extent of photoreceptor survival in mice of these four genotypes. Data
were collected separately from male and female sibs of seven litters.
Figure 2 shows the results of this
analysis. Photoreceptor survival was increased by ~100% in both male
and female rds:bcl mice compared with nontransgenic
rds mice. However, the effect of Bcl-2 expression on the
rds phenotype was significantly less than the complete
rescue observed in rds:113 males (Kedzierski et al., 1998).
Mosaic expression of rds/peripherin in rds:113 females
caused partial rescue of the rds phenotype, as described (Kedzierski et al., 1998). Coexpression of Bcl-2 with rds/peripherin in
rds:113+bcl females conferred no additional rescue
effect.
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Figure 2.
Quantitation of the number of photoreceptor
nuclei. Analysis was performed on 3-month-old male and female retinas
of the four genotypes: rds, rds:bcl,
rds:113, and rds:113+bcl. Data are presented as
means ± SEM (n = 6). Males:
ap < 0.001, rds:bcl
versus rds and rds:113. Females:
bp < 0.001, rds:bcl
versus rds; p < 0.05, rds:bcl versus rds:113.
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Photoreceptor survival in 1-month-old retinas
Approximately one-third of photoreceptors are lost during the
first postnatal month in rds retinas. We sought to determine whether the preponderance of photoreceptors lost in rds:bcl
mice occurred during this accelerated cell-death period. Accordingly, we compared the number of photoreceptor nuclei present at 35-38 d in
rds and rds:bcl mice. Morphometry was conducted
on retinas from rds males and females, five of each, and
rds:bcl males and females, four of each. The rds
retinas had an average of 50.8 ± 4.7 photoreceptor nuclei
(n = 5) per 50 µm, whereas the rds:bcl retinas had 66.6 ± 0.53 nuclei (n = 4) per 50 µm, representing a 31% increase. Thus, the protective effect of
Bcl-2 was present during the early phase of cell death. A comparison of
these values with the number of nuclei remaining at 3 months (23 ± 1.7 for rds and 47 ± 2.3 for
rds:bcl) indicates that photoreceptors continue to
die in rds:bcl mice during the ensuing 2 months, although at a slower rate than in rds mice.
Levels of transgenic Bcl-2 expression
To confirm the levels and stability of Bcl-2 expression, we
performed immunoblot analysis on retinal homogenates from
transgenic and nontransgenic mice at 2, 3, and 4 weeks of age.
These intervals bracket the period of accelerated photoreceptor
degeneration in rds mice. No difference was observed
in the levels of Bcl-2 in transgenic mice at these different ages (Fig.
3). Bcl-2 immunoreactivity was
undetectable in the nontransgenic littermates.
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Figure 3.
Immunoblot analysis showing the levels of Bcl-2 in
retinas from 2-, 3-, and 4-week-old mice on an
rds/ background. TG denotes
Bcl-2 transgenic, and nTG denotes nontransgenic. Note
the nearly adult levels of Bcl-2 expression in 2-week-old retinas.
w, Week.
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Ultrastructural analysis
We examined the effects of Bcl-2 expression on the cellular
organization of photoreceptors by electron microscopy. In
rds:bcl retinas, photoreceptors completely lacked outer
segments (Fig. 4A),
similar to those observed in nontransgenic rds mice (Jansen and Sanyal, 1984; Nir and Papermaster, 1986). Thus, the protective effect of Bcl-2 expression on photoreceptor death was not mediated by a
correction of the outer segment phenotype in rds mice. The antiapoptotic effect of Bcl-2 is manifested in the increased
number of photoreceptor nuclei. In the rds:113+bcl male
retina, the expression of the Bcl-2 transgene had no adverse effect on
the ultrastructure of outer segments (Fig. 4B).
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Figure 4.
Electron micrographs of 3-month-old mice.
A, Homozygous rds retina expressing Bcl-2
(rds:bcl). Note the absence of outer segments and
the abnormal position of photoreceptor rod inner segments
(RIS) against the retinal pigment epithelium
(RPE). The effect of Bcl-2 on photoreceptor survival is
evident by the presence of a significant number of photoreceptor nuclei
(N). B, Homozygous
rds retina expressing both normal rds/peripherin and
Bcl-2 transgenes (rds:113+bcl). Note the normal
morphology of intact rod outer segments (ROS) adjacent
to the RPE. The expression of Bcl-2 did not adversely
affect photoreceptor organization. Magnification: A, 3200×; B,
2900×.
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DISCUSSION |
In the present study, we examined the effect of Bcl-2 expression
on photoreceptor degeneration in rds mutant mice. At 3 months, mice expressing the Bcl-2 transgene retained approximately
twice the number of photoreceptors as did nontransgenic rds
mice. This is in contrast to previous studies on mice with null
mutations in the genes for the  - and  -subunits of cGMP
phosphodiesterase (PDE) and dominant mutations K269E and S334ter in the
gene for rhodopsin. Expression of Bcl-2 in these mice resulted in minor and transient increased photoreceptor survival (Chen et al., 1996; Joseph and Li, 1996; Tsang et al., 1997).
In the rd mouse, a mutation in the -subunit of PDE results in
accumulation of cGMP with severe metabolic consequences, leading to
early photoreceptor death. Apoptosis starts at postnatal day 7 (P7),
and by P20 almost all rods die (Carter-Dawson et al., 1978; Farber et
al., 1988; Portera-Cailliau et al., 1994). In the
Pdegtm1/Pdegtm1
mouse with a mutation in the -subunit of PDE, almost all cells die
between P14 and P21 (Tsang et al., 1996). In the opsin S334ter mutant, as in the rd mouse, the mutation leads to the onset of apoptosis at P8 and completion by P21 (Chen et al., 1996). In contrast
to these mutants, cell death in the rds retina starts at
P14-P17 and progresses slowly for a full year (Sanyal et al., 1980;
Nir et al., 1990). The increased effect of Bcl-2 expression on the
preservation of photoreceptors in rds mice may be caused by
the slower pace of apoptosis in this mutation. In assessing the
significance of the present data it should be noted that the rate of
cell death in rds mice more closely resembles the rate observed in human RP and other forms of progressive neuronal degeneration.
A key feature of the rds phenotype is absent outer segments
(Jansen and Sanyal, 1984; Nir and Papermaster, 1986), because of loss
of the structural protein rds/peripherin (Travis et al., 1989, 1991;
Connell et al., 1991). Not surprisingly, Bcl-2 expression did not
reverse the rds phenotype of absent outer segments (Fig. 4)
because expression of this antiapoptotic protein does not correct the
inherent genetic mutations leading to the structural defect. The
protective effect of Bcl-2 on photoreceptor survival must be by an
alternative mechanism. Because Bcl-2 was shown to protect against
diverse cytotoxic insults (Adams and Cory, 1998), it is not certain
what type of stress triggers apoptosis in the rds retina.
One possibility is that the absence of outer segments in rds
mice may predispose photoreceptors to oxygen toxicity. The loss of
outer segments might be accompanied by the loss of the cGMP-gated
cation channels and a dramatic reduction in cation influx. This may
"unload" the
Na+/K+ ATPase
pumps, resulting in significantly reduced oxygen consumption by inner
segment mitochondria and a much flatter pO2
gradient across the distal retina. Also, with the loss of outer
segments, the photoreceptor cell bodies are physically closer to the
oxygen-rich choriocapillaris. These two effects may conspire to produce
toxic levels of oxygen in the microenvironment of rds
photoreceptor cell bodies. The association between apoptotic cell death
and the presence of reactive oxygen species is well established. Bcl-2 was shown to prevent neuronal cell death by decreasing the net generation of oxygen species (Kane et al., 1993). Overexpression of
Bcl-2 suppressed lipid peroxidation completely (Hockenbery et al.,
1993). Also, in a study of Bcl-2-deficient mice, enhanced oxidative
stress and susceptibility to oxidants were found (Hochman et al.,
1998). Thus, Bcl-2 may be particularly effective in preventing cell
death attributable to oxidative damage.
Although expression of Bcl-2 in rds:bcl mice resulted in a
near doubling of surviving photoreceptors compared with that in nontransgenic rds mutants, only ~60% of the
photoreceptors were protected from degeneration compared with fully
rescued rds:113 male controls. This persistent cell loss was
probably not caused by direct Bcl-2 toxicity, because we observed
similar numbers of photoreceptors in rds:113 and
rds:113+bcl mice. In this study we used a low-expressing
Bcl-2-transgenic line (line B), which did not cause photoreceptor
degeneration on an otherwise wild-type genetic background (Chen et al.,
1996). Higher levels of Bcl-2, or additional members of the Bcl family
(besides Bcl-XL), may be required for complete
protection. Alternatively, it may be impossible fully to prevent
photoreceptor degeneration attributable to mutations in a critical gene
by expression of proteins that inhibit apoptosis.
We showed in a previous study that female mice hemizygous for the 113 transgene displayed a mosaic pattern of normal rds/peripherin expression, both by in situ hybridization and outer segment
ultrastructure, because of random inactivation of chromosome X
(Kedzierski et al., 1998). However, retinal degeneration in these mice
was uniform, with no mosaic pattern of cell loss. This observation
indicates a non-cell-autonomous component of photoreceptor degeneration in rds mice (Kedzierski et al., 1998). Before the current
study, we anticipated that Bcl-2 expression in rds:113+bcl
hemizygous females may preferentially protect photoreceptors that
express the rds rescue transgene, because these cells are
entirely normal in the context of transgenic male or homozygous female
retinas. This was not observed, however. Expression of Bcl-2 in
rds:113+bcl hemizygous females resulted in no additional
protection against photoreceptor degeneration compared with that in
rds:113 hemizygous females (Fig. 2). The degree of rescue in
rds:113 hemizygous females was higher here than in our
previous study (Kedzierski et al., 1998). This may be attributable to
strain effects on the time of X-chromosome inactivation, which would
affect the coarseness of the mosaic.
In summary, Bcl-2 had the greatest protective effect on unrescued
rds photoreceptors. Because rds photoreceptors
fail to form outer segments (Jansen and Sanyal, 1984; Nir and
Papermaster, 1986), we suggest that the major activity of Bcl-2 is to
protect against oxygen-mediated toxicity. Shortening of outer segments is an ultrastructural feature of multiple inherited retinal
degenerations, including several that affect humans (Travis, 1998). The
results of this study suggest that somatic gene therapy involving the delivery of Bcl-2 to diseased photoreceptors may slow the progression in some forms of human inherited blindness.
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FOOTNOTES |
Received Nov. 2, 1999; revised Dec. 28, 1999; accepted Jan. 5, 2000.
This work was supported by National Institutes of Health (NIH)
Grant EY10286 to I.N., NIH Grant EY08043 and a grant from the Foundation Fighting Blindness to G.H.T., and NIH Grants EY12155 and
EY12703 and grants from the Ruth and Milton Steinbach Fund and Research
to Prevent Blindness to J.C. We thank Annemarie Brown and Roxana Radu
for their excellent technical support.
Correspondence should be addressed to Dr. Izhak Nir, Department of
Pharmacology, University of Texas Health Science Center, San Antonio,
TX 78284. E-mail: nir{at}uthscsa.edu.
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REFERENCES |
-
Abler AS,
Chang CJ,
Ful J,
Tso MO,
Lam TT
(1996)
Photic injury triggers apoptosis of photoreceptor cells.
Res Commun Mol Pathol Pharmacol
92:177-189[ISI][Medline].
-
Adams JM,
Cory S
(1998)
The Bcl-2 protein family: arbiters of cell survival.
Science
281:1322-1326[Abstract/Free Full Text].
-
Carter-Dawson LD,
LaVail MM,
Sidman RL
(1978)
Different effect of the rd mutation on rods and cones in the mouse retina.
Invest Ophthalmol Vis Sci
17:489-498[Abstract/Free Full Text].
-
Chang G-Q,
Hao Y,
Wong F
(1993)
Apoptosis: final common pathway of photoreceptor death in rd, rds and rhodopsin mutant mice.
Neuron
11:595-605[ISI][Medline].
-
Chen J,
Flannery JG,
LaVail MM,
Steinberg RH,
Xu J,
Simon MI
(1996)
bcl-2 overexpression reduces apoptotic photoreceptor cell death in three different retinal degenerations.
Proc Natl Acad Sci USA
93:7042-7047[Abstract/Free Full Text].
-
Connell G,
Bascom R,
Molday R,
Reid D,
McInnes RR,
Molday RS
(1991)
Photoreceptor peripherin is the normal product of the gene responsible for retinal degeneration in the rds mouse.
Proc Natl Acad Sci USA
88:732-736[Abstract/Free Full Text].
-
Cook B,
Lewis GP,
Fisher SK,
Adler R
(1995)
Apoptotic photoreceptor degeneration in experimental retinal detachment.
Invest Ophthalmol Vis Sci
36:990-996[Abstract/Free Full Text].
-
Farber DB,
Sunmin P,
Yamashita C
(1988)
Cyclic GMP-phosphodiesterase of rd retina: biosynthesis and content.
Exp Eye Res
46:363-374[Medline].
-
Hochman A,
Sternin H,
Gorodin S,
Korsmeyer S,
Ziv I,
Melamed E,
Offen D
(1998)
Enhanced oxidative stress and altered antioxidants in the brain of Bcl-2 deficient mice.
J Neurochem
71:741-748[ISI][Medline].
-
Hockenbery DM,
Oltvai ZN,
Yin X-M,
Milliman CL,
Korsmeyer SJ
(1993)
Bcl-2 functions in an antioxidant pathway to prevent apoptosis.
Cell
75:241-251[ISI][Medline].
-
Jansen HG,
Sanyal S
(1984)
Development and degeneration of retina in rds mutant mice: electron microscopy.
J Comp Neurol
224:71-84[ISI][Medline].
-
Joseph RM,
Li T
(1996)
Overexpression of Bcl-2 or Bcl-XL transgenes and photoreceptor degeneration.
Invest Ophthalmol Vis Sci
37:2434-2446[Abstract/Free Full Text].
-
Kane DJ,
Sarafian TA,
Anton R,
Hahn H,
Gralla EB,
Valentine JS,
Ord T,
Bredesen DE
(1993)
Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species.
Science
262:1274-1277[Abstract/Free Full Text].
-
Kedzierski W,
Bok D,
Travis GH
(1998)
Non-cell-autonomous photoreceptor degeneration in rds mutant mice mosaic for expression of a rescue transgene.
J Neurosci
18:4076-4082[Abstract/Free Full Text].
-
Kedzierski W,
Weng J,
Travis GH
(1999)
Analysis of the rds/peripherin-rom1 complex in transgenic photoreceptors that express a chimeric protein.
J Biol Chem
274:29181-29187[Abstract/Free Full Text].
-
Keen TJ,
Inglehearn CF
(1996)
Mutations and polymorphisms in the human peripherin-RDS gene and their involvement in inherited retinal degeneration.
Hum Mutat
8:297-303[ISI][Medline].
-
Kluck RM,
Bossy-Wetzel E,
Green DR,
Newmeyer DD
(1997)
The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis.
Science
275:1132-1136[Abstract/Free Full Text].
-
Krippner A,
Matsuno-Yagi A,
Gottlieb RA,
Babior BM
(1996)
Loss of function of cytochrome c in Jurkat cells undergoing fas-mediated apoptosis.
J Biol Chem
271:21629-21636[Abstract/Free Full Text].
-
Levin LA,
Schlamp CL,
Spieldoch RL,
Geszvain KM,
Nickells RW
(1997)
Identification of the bcl-2 family of genes in the rat retina.
Invest Ophthalmol Vis Sci
38:2545-2553[Abstract/Free Full Text].
-
Li P,
Nijhawan D,
Budihardjo I,
Srinivasula SM,
Ahmad M,
Alnemri ES,
Wang X
(1997)
Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade.
Cell
91:479-489[ISI][Medline].
-
Lolley RN,
Rong H,
Craft CM
(1994)
Linkage of photoreceptor degeneration by apoptosis with inherited defect in phototransduction.
Invest Ophthalmol Vis Sci
35:358-362[Abstract/Free Full Text].
-
Molday SM
(1998)
Photoreceptor membrane proteins, phototransduction, and retinal degenerative diseases.
Invest Ophthalmol Vis Sci
39:2493-2513.
-
Molthagen M,
Schachner M,
Bartsch U
(1996)
Apoptotic cell death of photoreceptor cells in mice deficient for the adhesion molecule on glia (AMOG, the beta 2-subunit of the Na, K-ATPase).
J Neurocytol
25:243-255[ISI][Medline].
-
Nir I,
Papermaster DS
(1986)
Immunocytochemical localization of opsin in the inner segment and ciliary plasma membrane of photoreceptors in retinas of rds mutant mice.
Invest Ophthalmol Vis Sci
27:836-840[Abstract/Free Full Text].
-
Nir I,
Agarwal N,
Papermaster DS
(1990)
Opsin gene expression during early and late phases of retinal degeneration in rds mice.
Exp Eye Res
51:257-267[ISI][Medline].
-
Portera-Cailliau C,
Sung C-H,
Nathans J,
Adler R
(1994)
Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa.
Proc Natl Acad Sci USA
91:974-978[Abstract/Free Full Text].
-
Reuter JH,
Sanyal S
(1984)
Development and degeneration of retina in rds mutant mice: the electroretinogram.
Neurosci Lett
48:231-237[ISI][Medline].
-
Sanyal S,
De Ruiter A,
Hawkins RK
(1980)
Development and degeneration of retina in rds mutant mice: light microscopy.
J Comp Neurol
194:193-207[ISI][Medline].
-
Shastry BS
(1997)
Signal transduction in the retina and inherited retinopathies.
Cell Mol Life Sci
53:419-429[ISI][Medline].
-
Travis GH
(1998)
Mechanism of cell death in the inherited retinal degenerations.
Am J Hum Genet
62:503-508[ISI][Medline].
-
Travis GH,
Brennan MB,
Danielson PE,
Kozak CA,
Sutcliffe JG
(1989)
Identification of a photoreceptor-specific mRNA encoded by the gene responsible for retinal degeneration slow (rds).
Nature
338:70-73[Medline].
-
Travis GH,
Sutcliffe JG,
Bok D
(1991)
The retinal degeneration slow (rds) gene product is a photoreceptor disc membrane-associated glycoprotein.
Neuron
6:61-70[ISI][Medline].
-
Travis GH,
Groshan KR,
Lloyd M,
Bok D
(1992)
Complete rescue of photoreceptor dysplasia and degeneration in transgenic retinal degeneration slow (rds) mice.
Neuron
9:113-119[ISI][Medline].
-
Tsang SH,
Gouras P,
Yamashita CK,
Kjeldbye H,
Fisher J,
Farber DB,
Goff SP
(1996)
Retinal degeneration in mice lacking the g-subunit of the rod cGMP phosphodiesterase.
Science
272:1026-1029[Abstract].
-
Tsang SH,
Chen J,
Kjeldbye H,
Li W,
Simon MI,
Gouras P,
Goff SP
(1997)
Retarding photoreceptor degeneration in Pdegtm1/Pdegtm1 mice by an apoptosis suppressor gene.
Invest Ophthalmol Vis Sci
38:943-950[Abstract/Free Full Text].
-
Tso MOM,
Zhang C,
Abler AS,
Chang CJ,
Wong F,
Chang GQ,
Lam TT
(1994)
Apoptosis leads to photoreceptor degeneration in inherited retinal dystrophy of RCS rats.
Invest Ophthalmol Vis Sci
35:2693-2699[Abstract/Free Full Text].
-
Yang J,
Liu X,
Bhalla K,
Kim CN,
Ibrado AM,
Cai J,
Peng TI,
Jones DP,
Wang X
(1997)
Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked.
Science
275:1129-1132[Abstract/Free Full Text].
Copyright © 2000 Society for Neuroscience 0270-6474/00/2062150-05$05.00/0
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