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1 From the Neurophysiology, and 2 Retinal Cell Biology Laboratories, Department of Ophthalmology, University Hospital Zurich, Switzerland; and the 3 Department of Biology and Biochemistry, College of Optometry, University of Houston, Texas.
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Abstract |
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METHODS. Retinal function was evaluated in dark-adapted mice by full-field electroretinograms (ERGs) over more than 6 log units of intensity. Retinal morphology was studied by light- and electron microscopy. Arrestin and the heat shock protein 70 (Hsp70) were detected by Western blot analysis. The rhodopsin content and the kinetics of rhodopsin regeneration were determined in retinal extracts.
RESULTS. Although the configuration of the ERGs was comparable in both groups of mice, c-fos-/- mice showed a marked variability in all quantitative ERG-measures with lower mean amplitudes, longer latencies, and a 0.9-log-unit lower b-wave sensitivity on average. Morphometry showed that c-fos-/- mice have 23% fewer rods on average, whereas the number of cones was comparable among c-fos+/+ and c-fos-/- mice. Arrestin levels appeared slightly reduced in c-fos-/- mice when compared with c-fos+/+ mice, whereas Hsp70 levels were comparable in both genotypes. The kinetics of rhodopsin regeneration were similar, but c-fos-/- mice had a 25% lower rhodopsin content on average.
CONCLUSIONS. Compared with c-fos+/+ mice, retinal function in c-fos-/- mice is attenuated to a variable but marked degree, which may be, at least in part, related to the reduced number of rods and the reduced rhodopsin content. However, c-fos does not appear to be essential for the ability to absorb photons, nor for phototransduction or the function of second-order neurons. The resistance to light-induced apoptosis of photoreceptor cells in c-fos-/- mice may result from the acute deficit of c-fos in the apoptotic cascade rather than from developmental deficits affecting rod photoreceptor function.
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Introduction |
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During apoptosis the immediate early gene and proto-oncogene c-fos is induced in several systems.4 5 c-fos encodes the phosphoprotein c-Fos, a component of the nuclear transcription factor complex AP-1, which modulates the expression of a variety of genes also in the retina.6 7 8 However, the physiological function of c-Fos in the retina remains to be investigated.
Under a regular dark–light cycle, retinal c-fos is expressed in a diurnal rhythm. c-fos is induced in the ganglion cell layer and in the inner nuclear layer after the onset of light but in the outer nuclear layer (ONL) during the dark period.9 10 11
Recently, it has been shown that c-fos plays an essential role in light-induced apoptosis of photoreceptors: after exposure to bright white light, wild-type mice (c-fos+/+ mice) display severe loss of photoreceptor cells due to apoptosis, whereas retinas of mice without c-Fos (c-fos-/- mice) remain unaffected.12 The observed resistance to light-induced apoptosis in c-fos-/- mice may indicate an active contribution of c-Fos to the apoptotic cascade triggered by light. Because c-Fos is suggested to play an important role in the regulation of rod-specific gene expression,13 functional deficits in c-fos-/- mice may render their retinas insensitive to light. Finally, given the deficits in bone and cartilage development with reduced body weight,14 it could be assumed that c-fos-/- mice are under constant stress. Stress may induce the expression of heat shock proteins that have been suggested to be involved in the resistance against light damage.15
To date, no information about functional properties of the retina in c-fos-/- mice is available. To elucidate the mechanism rendering c-fos-/- mice resistant to light-induced apoptosis, we compared the retina of c-fos-/- and c-fos+/+ mice in their ability to absorb and transduce light. We studied retinal function by full-field electroretinograms (ERGs), and we compared retinal morphology by light and electron microscopy. We furthermore investigated critical components related to photoreception and phototransduction: the rhodopsin content and regeneration rate, the retinal photon absorption capacity, and the levels of arrestin, which deactivates rhodopsin.16 17 To detect a possible candidate with protective potential against light damage, we furthermore determined the level of Hsp70.
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Methods |
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Electroretinography
Sixteen male mice (eight
c-fos+/+, eight
c-fos-/-) were used for
electroretinography, performed in a standardized timing and anesthesia
protocol. After a 16-hour period of dark adaptation, mice underwent ERG
recording. Body weight was measured before anesthesia, which was
performed with a single intraperitoneal injection of xylazine (20
µg/g) and ketamine (40 µg/g). Mice were placed on a 38°C heating
pad throughout the experimental session. After dilation of the pupils
(Mydriaticum Dispersa; Ciba Vision, Niederwangen, Switzerland),
full-field ERGs were recorded from the left eye using a silk Ag-AgCl
electrode18
placed centrally on the cornea. The reference
electrode was placed in the mouth, and a needle electrode in the tail
served as a ground. All manipulations were performed under very dim red
light using an operating microscope. The position of the electrode was
monitored with an infrared camera. White light stimuli of a
halogen-source (model 150H; Volpi, Schlieren, Switzerland) of 20-msec
duration were presented in order of increasing luminance over a range
of 6 logarithmic units of intensity (8 x
10-2 to 8 x 104
candela [cd]/m2). Four consecutive responses
were averaged with an interstimulus interval of 5 seconds for the a-
and b-wave and with an interval of 7 seconds for the c-wave. Signals
were digitized by a personal computer for off-line
analysis19
and written on a chart recorder (Kipp & Zonen;
Recom Electronics, Horgen, Switzerland). The amplitude of the a-wave
was measured from the prestimulus baseline to the trough of the a-wave.
The amplitude of the b-wave was measured either from the trough of the
a-wave to the positive peak or, at low intensities, from the baseline
to the positive peak. Higher stimulus intensities evoked prominent
oscillatory potentials that contributed to the amplitude of the b-wave.
To obtain an unequivocal assessment of the time course of the b-wave,
we therefore measured its latency from the time of the stimulus onset
to the time of the beginning of the b-wave instead of measuring the
implicit time. After the ERG recording, some of the mice were used for
morphologic studies.
Morphology
Light microscopy was performed as described
previously.12
Briefly, eyes were enucleated and fixed in
2.5% glutaraldehyde in 0.1 M cacodylate buffer (pH 7.3) at 4°C
overnight. For each eye, the superior and the inferior central retina
adjacent to the optic nerve was trimmed, washed in cacodylate buffer,
postfixed in osmium tetroxide for 1 hour, dehydrated in increasing
ethanol concentrations, and embedded in Epon 812. Sections (0.5 µm)
were prepared from the superior and the inferior central retina,
stained with methylene blue, and analyzed by microscopy (Axiophot;
Zeiss, Oberkochen, Germany). For a comparison of rod outer segment
(ROS) length, in every second of 10 photographs (x740), each
representing 125 µm, the distance from the ROS bases to the tips of
the ROS layer adjacent to the RPE was determined.
For electron microscopy, eyes were removed and fixed by immersion fixation using 3% glutaraldehyde, 2% paraformaldehyde, and 0.1% CaCl2 in 0.1M cacodylate buffer (pH 7.4). The tissue was embedded in Spurr’s epoxy medium. Ultrathin sections were stained with 3.5% uranyl acetate and Reynold’s lead citrate and examined using a transmission electron microscope (model 100-C; JEOL, Tokyo, Japan). Morphometry was performed on Spurr’s embedded 1.2-µm sections stained with toluidine blue using a x40 objective lens (total magnification, x400) and a calibrated Filar micrometer eyepiece on a stereomicroscope (model BH-2; Olympus, Melville, NY). Counts of rod and cone photoreceptor nuclei were made at the posterior pole of the eye (central retina) and in the periphery of both the superior and the inferior temporal quadrants, as described earlier.20 Twenty fields, each 100 µm in length, were examined in each of three sections from five c-fos+/+ and four c-fos-/- mice: 10 beginning 100 µm from the optic nerve head and moving peripherally and another 10 beginning 100 µm from the ora serrata and moving posteriorly. The number of rod and cone photoreceptor cells was recorded in each region, and the mean was calculated for each animal. Then, the overall group mean, SEM, and percentage of each cell type were calculated.
Rhodopsin Content and Rhodopsin Regeneration
For the determination of the maximal rhodopsin contents mice were
dark adapted for 16 hours. All subsequent manipulations were conducted
under dim red light. Both retinas from one mouse were removed through a
corneal slit and pooled in 1 ml ddH2O. After
centrifugation (15,000g, 3 minutes, 19°C) the supernatant
was discarded, and retinas were resuspended in 0.7 ml 1%
hexadecyltrimethyl-ammoniumbromide (Fluka Chemie, Buchs, Switzerland)
in ddH2O, homogenized with a polytron (20
seconds, 3000 rpm) and centrifuged as above.21
The
absorption at 500 nm of the resultant supernatant was measured in a
spectrophotometer (Cary 50, Varian; Zug, Switzerland), using a plastic
cuvette (path length, 1 cm). After exposing the sample to intense white
light (20,000 lux) for 1 minute to bleach all present rhodopsin, the
spectrophotometric measurement was repeated. The amount of rhodopsin
present per retina was calculated using the following formula derived
from the Lambert–Beer equation:
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abs500 is the difference between absorption
before and after bleaching measured at 500 nm; e is the
extinction coefficient of rhodopsin at 500 nm (4.2 x
104 cm x M); l is the path length of
the plastic cuvette (in centimeters); and n is the number of
retinas. To assess the regeneration kinetics of rhodopsin in vivo, pupils of animals were dilated under dim red light (Cyclogyl 1%; Alcon, Cham, Switzerland; and phenylephrine 5%, Ciba Vision, Niederwangen, Switzerland) after 16 hours of dark adaptation, and animals were exposed to 5000 lux diffuse white fluorescent light (TLD-36 tubes; Philips, Hamburg, Germany; UV-impermeable diffuser) in cages with a reflective interior for 10 minutes. Rhodopsin content was determined immediately (0 minutes, nearly complete bleaching) or after 5, 10, 15, 30, 60, 120, and 240 minutes (c-fos+/+ ) and 0, 30, 60, and 240 minutes (c-fos-/-) in darkness, as described. Using those values for rhodopsin per retina (Table 1) , the resultant regeneration constants and the number of photons absorbed per 10 minutes by mice of both genotypes were calculated for the steady state of bleaching, as described by Penn and Williams.22
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Results |
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Rhodopsin Content and Rhodopsin Regeneration: Number of Photons
Absorbed
A significant reduction of 25% in rhodopsin content was found in
c-fos-/- mice (Table 1
, P < 0.001, two-way analysis of variance) when compared with
c-fos+/+ mice. Almost complete bleaching
was achieved in dark-adapted animals within 10 minutes of exposure to
5000 lux (c-fos+/+,
94% bleached;
c-fos-/-, 92% bleached). Bleached
rhodopsin was nearly entirely regenerated during 240 minutes in
darkness (c-fos+/+, 92%;
c-fos-/-, 98%).
The regeneration rates for rhodopsin calculated from the values displayed in Table 1 were 0.01 per minute for c-fos+/+ and 0.016 per minute for c-fos-/-, indicating a slightly faster regeneration in c-fos-/- mice. Because the calculation of the number of photons absorbed22 is only appropriate if bleaching versus regeneration is in a steady state, rhodopsin levels during bleaching were determined for wild-type mice at 10 minutes, 30 minutes, and 60 minutes. No difference in rhodopsin levels per retina was observed among the three time points (10 minutes, 0.03 nanomoles; 30 minutes, 0.03 nanomoles; 60 minutes, 0.04 nanomoles; n = 3 for 30 and 60 minutes; not shown), indicating that the steady state is reached at 10 minutes and exists for at least 60 minutes.
The calculation of the number of photons absorbed at steady state gave the following results: c-fos+/+ mice absorbed 2.9 x 1013 photons and c-fos-/- absorbed 3.4 x 1013 photons per retina per 10 minutes of exposure to 5000 lux.
Immunodetection of Arrestin and Hsp70
A very slight reduction in arrestin levels was detected in
extracts from c-fos-/- mice, judged by
comparing band staining intensities on Western blot analysis between
c-fos+/+ and
c-fos-/- mice (Fig. 5)
. The Hsp70-antiserum detected comparable amounts of the constitutive
form of Hsp70 (Hsc70, 73 kDa) in extracts of both genotypes. After
prolonged exposure of the x-ray film, a faint band corresponding to the
inducible form of Hsp70 (Hsp70, 72 kDa) became visible. No apparent
difference was observed between c-fos+/+
and c-fos-/- mice (Fig. 5)
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Discussion |
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Variability in c-fos-/- Mice
c-fos-/- mice display a remarkable
variability of all electrophysiological data. Similarly, we observed a
larger variability in body weight of age-matched
c-fos-/- mice than in wild-type mice
(±35.3% SD in c-fos-/- mice, ±19.9% SD in
c-fos+/+ mice; n = 8 each). The
lower variability observed in c-fos+/+ mice
grown on an identical genetic background, indicates a higher
sensitivity to epigenetic influences in
c-fos-/- mice. These observations of
phenotypic heterogeneity complement the results of behavioral tests in
these mice.27
Electroretinography
The normal configuration of the full-field ERG-recordings of
c-fos+/+ and
c-fos-/- mice demonstrates photoreceptor
activity (a-wave), inner retinal activity (b-wave and oscillatory
potentials), and a functional photoreceptor-RPE interaction (c-wave).
These results indicate that c-fos is not essential for the
ability to absorb photons, for phototransduction or for the function of
second-order neurons. It is evident, however, that retinal function in
c-fos-/- mice is attenuated markedly,
resulting in lower mean amplitudes, longer mean latencies, and reduced
retinal sensitivity. This attenuation in retinal sensitivity in
c-fos-/- mice amounts to 0.2 log units
for the a-wave and to 0.9 log units for the b-wave, indicating a larger
postreceptoral functional difference between
c-fos+/+ and
c-fos-/- mice. At higher luminances the
mean latencies in the two genotypes differed less than at lower
luminances. Based on pure rod responses at lower luminances but an
increasing contribution of the cone system at higher luminances, the
functional differences between both genotypes therefore may affect the
rod system rather than the cone system. This suggestion would
correspond to a reduced number of rods, a lower rhodopsin content, and
an unaltered number of cones observed in
c-fos-/- mice.
Morphology
c-fos-/- mice display a selective
reduction of rod photoreceptors with no preference for any retinal
area. This reduction may occur because of a reduced differentiation of
precursor cells into rods or because of increased developmental
apoptosis. However, because of a grossly unaltered morphology, it
appears that developmental apoptosis in the retina proceeds normally in
the absence of c-fos, suggesting that other proteins of the
AP-1 family can substitute for the absence of c-fos during
development. Our observation thus complements an earlier
report.28
Rhodopsin Content and Regeneration
The values of rhodopsin determined after 16 hours of dark
adaptation are likely to reflect maximal values in
c-fos+/+ and
c-fos-/- mice, because both types of mice
almost completely regenerated rhodopsin within 4 hours after bleaching.
The rhodopsin content in c-fos-/- mice
was reduced by 25% in dark adaptation. Because a shortening of ROS, at
least in central areas, was not observed, it appears likely that this
reduction is based solely on the absence of 22% to 24% rods in these
animals. Thus, at the level of single cells, the individual rod in
c-fos-/- mice is most likely furnished
with the same amount of rhodopsin as is its wild-type counterpart.
Arrestin
Activated rhodopsin may stimulate the phototransduction cascade
differently in c-fos+/+ compared with
c-fos-/- mice, for example, because of
deviant deactivation kinetics. The deactivation of rhodopsin depends on
arrestin,16
and increased levels of arrestin in ROS have
been associated with reduced retinal sensitivity.29
Arrestin is exclusively expressed in photoreceptors. Accordingly, a
reduction of arrestin immunoreactivity might be expected in extracts
from c-fos-/- mice corresponding to the
loss of 23% rods. However, as judged by visual impression, the
reduction of band staining for arrestin on Western blots of
c-fos-/- retinal extracts appeared less
prominent. Thus, rods of c-fos-/- mice
may contain slightly elevated arrestin levels and therefore have an
increased ratio of arrestin to rhodopsin. This, however may not
influence the deactivation of rhodopsin: Studies in transgenic mice
indicate that binding of arrestin to photoisomerized rhodopsin is not
rate-limiting in quenching the activity of rhodopsin.17
Relations between Functional Parameters, Rhodopsin Content, and
Morphology
Several reports demonstrate that changes in rhodopsin content are
accompanied by functional and morphologic deficits of photoreceptor
cells.30
31
32
33
Changes in rhodopsin content due to an
increased background intensity, after bleaching, or under vitamin A
deficiency have been shown to raise threshold for ERG criterion
responses in a systematic manner.34
35
36
In correspondence,
attenuated retinal function in c-fos-/-
mice in our study was associated with a lower rhodopsin content and
with a reduction in the number of rods.
Whether this attenuation is primarily caused by the reduction in the number of rods and/or rhodopsin or whether components of the phototransduction cascade other than rhodopsin are also differently expressed in c-fos-/- mice remains to be investigated. It appears also conceivable that postreceptoral processes contribute to the differences in retinal function in c-fos+/+ and c-fos-/- mice.
Resistance to Light Damage in c-fos-/-
Mice
The susceptibility to light damage is determined by several
factors37
38
and may be reduced by protective mechanisms
such as upregulated heat shock proteins.15
We determined the levels of Hsc70 and Hsp70, which are members of the Hsp70 family. Both show antiapoptotic properties,39 40 41 and particularly Hsp70 has been suggested to be involved in the resistance against light damage.15 Assuming that in mice Hsp70 is primarily expressed in the ONL, as is the case in rats,42 a reduction of the inducible form of Hsp70 in c-fos-/- mice might be expected, corresponding to the loss of 23% of the rods. Thus, similar levels of Hsp70 in extracts from retinas of c-fos+/+ and c-fos-/- mice may suggest that it is elevated in the remaining rods of c-fos-/- mice. Nevertheless, it appears unlikely that a maximum increase of 23% accounts for the complete protection of rods against light-induced apoptosis. In this regard, a 20% increased expression of Hsp70 did not confer resistance against various apoptotic stimuli in cultured murine fibrosarcoma cells, whereas five- to sixfold elevated Hsp70 levels made these cells resistant.41
c-fos-/- mice showed attenuated but normally configured ERGs. It is not clear whether or to what extent this attenuation influences the susceptibility to light damage.
Although light damage may be rhodopsin mediated,43 it appears unlikely that the resistance to light-induced damage in c-fos-/- mice depends exclusively on a 25% reduced rhodopsin content. This assumption is supported by the following observations: First, the maximal rhodopsin value found in c-fos-/- (0.45 nanomoles) exceeds the lowest value found in c-fos+/+ mice (0.41 nanomoles). However, all c-fos+/+ mice tested in our laboratory so far (n > 50) showed light damage, but c-fos-/- mice never did (n > 30). Second, the calculation of the number of photons absorbed per retina per time, revealed comparable abilities to absorb photons at 5000 lux, perhaps because of the slightly faster regeneration of rhodopsin and despite its decreased dark-adapted levels in c-fos-/- mice. Interestingly, 50 minutes of exposure to this intensity are sufficient to induce light damage in c-fos+/+ mice (Wenzel A, Remé CE, Williams TP, Hafezi F, Grimm C, unpublished data, January–March, 1998). Furthermore, because the retina of c-fos-/- mice contains less rods, its individual rod may absorb even more photons during this time than a rod of a c-fos+/+ mouse. However, rods of c-fos-/- mice are protected against light-induced apoptosis, indicating that the signaling cascade leading from bleaching of rhodopsin to the induction of apoptosis is interrupted downstream of rhodopsin because of the absence of c-fos.
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Acknowledgements |
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Footnotes |
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Submitted for publication December 18, 1998; revised June 18 and August 16, 1999; accepted September 3, 1999.
Commercial relationships policy: N.
Corresponding author: Nicole Kueng–Hitz, Neurophysiology Laboratory, Department of Ophthalmology, University Hospital Zurich, Frauenklinikstrasse 24, CH-8091 Zurich, Switzerland. nicole.kueng{at}aug.usz.ch
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