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PubMed2005

The evolution and function of blue and red light photoreceptors.

Photoreceptors allow living organisms to optimize perception of light in the natural environment and thus to gain information about their external world. In this review, we describe blue and red light photoreceptors in bacteria, plants, and animals in relation to their evolution. Analyses performed in different organisms have revealed wonderful examples of structural modifications of the light-sensing proteins themselves, as well as diversification of the signal transduction pathways they use in relation with their evolutionary history and function. In different organisms, the same photoreceptor may have a very conserved role (convergent evolution of function) or may modulate different responses (acquisition of new function). Multiple photoreceptors of the same family in the same organism indicate gene duplication events during evolution, with a consequent enhanced sensitivity to variations in ambient light. Conversely, two different photoreceptors may be involved in the control of the same physiological response. Genomic analysis in marine diatoms, combined with phylogenetic studies, has also revealed the presence of blue and red light photoreceptors in the marine environment. This discovery has intriguing implications for the understanding of light perception and its evolution in photosynthetic organisms. In addition, the characterization of these photoreceptors likely will add to our understanding of photoreceptor diversity as an adaptation to different habitats.

Animals↗
PubMed2000

Targeted disruption of Müller cell metabolism induces photoreceptor dysmorphogenesis.

Within the retina, the Müller cells and photoreceptors are in close physical proximity and are metabolically coupled. It is unknown, however, whether Müller cells affect photoreceptor differentiation and outer segment membrane assembly. The objective of this study was to determine whether targeted disruption of Müller cell metabolism would induce photoreceptor dysmorphogenesis. Intact isolated Xenopus laevis embryonic eyes were cultured in medium with or without Müller cell-specific inhibitors (i.e., alpha-aminoadipic acid and fluorocitrate). To assess Müller cell injury, the gross retinal morphology was examined along with immunocytochemical assessment of Müller cell-specific protein expression patterns. The steady-state levels of opsin were quantified to determine whether the Müller cell inhibitors negatively affected photoreceptor protein synthesis. Müller and photoreceptor cell ultrastructure was scrutinized and the organization of the outer segment membranes was graded. In control retinas, there was no swelling of Müller cell cytoplasm. Glial fibrillary acidic protein (GFAP) was undetectable, whereas glutamine synthetase was abundant. The steady-state level of opsin was high and photoreceptors elaborated properly folded outer segments. Exposure to both Müller cell-specific inhibitors induced swelling of Müller cell endfeet, cytoplasmic paling and alterations of Müller cell-specific protein expression patterns. The steady-state level of opsin in retinas exposed to alpha-aminoadipic acid was unchanged compared with control eyes, whereas, in eyes exposed to fluorocitrate, opsin levels were slightly reduced. The most significant finding was that targeted disruption of Müller cell metabolism adversely affected photoreceptor outer segment membrane assembly, causing dysmorphogenesis of nascent outer segments. These results suggest that the termination signal(s) necessary for proper outer segment folding were disrupted by targeted inhibition of Müller cells and support the hypothesis that Müller cells interact with photoreceptors through mechanisms that may regulate, at least in part, the assembly of photoreceptor outer segment membranes.

2-Aminoadipic Acid↗
PubMed1993

Photoreceptor degeneration and altered distribution of interphotoreceptor matrix proteoglycans in the mucopolysaccharidosis VII mouse.

Recent studies suggest that chondroitin sulfate proteoglycans in the retinal interphotoreceptor matrix (IPM) play a role in maintaining photoreceptor viability. We report herein studies on the retinas from mice with mucopolysaccharidosis type VII (MPS VII), a storage disorder resulting from virtual absence of beta-glucuronidase, an enzyme that is involved in the lysosomal degradation of chondroitin sulfate and other beta-glucuronide-containing proteoglycans. The distribution of IPM chondroitin sulfate proteoglycans was examined by immunohistochemistry and lectin-based histochemistry, and compared with the morphology of photoreceptor and retinal pigmented epithelial (RPE) cells at various ages in MPS VII-affected mice. A number of lectins and antibodies were employed that react with epitopes of IPM chondroitin sulfate proteoglycans, including Triticum vulgaris agglutinin (WGA), Arachis hypogaea agglutinin (PNA), Phaseolus vulgaris agglutinin (PHA-L), and an antibody directed against chondroitin 6-sulfate (AC6S). In MPS VII-affected animals, slight shortening of photoreceptor outer segments occurs between postnatal months 1 and 8. This is associated with changes in the distribution of some of the IPM chondroitin sulfate proteoglycans and hypertrophy of the retinal pigmented epithelium due to the accumulation of cytoplasmic membrane-bounded vesicles. WGA- and PHA-L-, but not AC6S-binding glycoconjugates accumulate within the RPE of affected mice during this time. Immunoreactive chondroitin 6-sulfate is not observed within the RPE of affected animals, probably since the antibody employed does not label free chondroitin sulfate glycosaminoglycan fragments. A loss of the normal apical-basal distribution of chondroitin 6-sulfate and PHA-L-binding IPM proteoglycans is apparent by 4 postnatal months. In contrast, WGA-binding proteoglycan remains uniformly distributed through 8 months. Pyknotic photoreceptor nuclei are observed in months 2-5 and photoreceptor loss is observed by 6 months. Cone photoreceptor loss appears to occur prior to that of rod photoreceptors. These observations suggest that the absence of beta-glucuronidase in the RPE of MPS VII mice may lead to an altered distribution of at least some IPM chondroitin sulfate proteoglycans. The resultant changes in the biochemical composition and/or physical structure of the IPM may affect subsequently its photoreceptor cell-supportive function leading to photoreceptor degeneration.

Animals↗
PubMed1996

Basic fibroblast growth factor: increased gene expression in inherited and light-induced photoreceptor degeneration.

In a recent study, we reported that bFGF content and mRNA expression levels are elevated in degenerating photoreceptors in the rd mouse retina as compared to the levels in photoreceptors in age matched normal retinas (Gao and Hollyfield, 1995). To determine whether bFGF up-regulation is a general feature of degenerating photoreceptors, bFGF expression was examined with in situ hybridization in several rodent models with retinal degeneration: (a) the normal mouse retina in which cGMP metabolism had been disrupted pharmacologically using an inhibitor of phosphodiesterase or an analog of cGMP, (b) the rds mouse with an inherited photoreceptor degeneration that does not involve alterations in cGMP metabolism, (c) light-damaged BALB/c mice subjected to bright constant light, and (d) light-stressed albino rats subjected to bright cyclic light. In each of these models, we observed dramatic up-regulation of bFGF gene expression in photoreceptors, although the relative levels varied among the different models and followed different temporal patterns. We conclude that increased expression of bFGF in photoreceptors during their degeneration is a general phenomenon occurring in rd, rds, light-damaging and light-stressing conditions. These observations indicate that bFGF can be up-regulated by a variety of photoreceptor insults. We speculate that endogenous bFGF may function as a photoreceptor protection/rescue factor that is activated in response to photoreceptor stress.

Animals↗
PubMed2001

Regulation of cAMP by light and dopamine receptors is dysfunctional in photoreceptors of dystrophic retinal degeneration slow(rds) mice.

cAMP levels in dark and light were studied in dystrophic retinal degeneration slow(rds) mice, which carry a mutation in the rds/peripherin gene. cAMP levels were measured in vivo, in freshly isolated retinas, and in vitro in the presence of glutamate, which confines light modulation to photoreceptors. Experiments were conducted on young animals, when significant numbers of viable photoreceptor cells are present. In vivo levels of cAMP are higher in illuminated rds/rds retinas than levels measured in normal BALB/c retinas. Light-evoked down-regulation of cAMP levels was observed in vitro in normal photoreceptors. These measurements were made in the presence of the cyclic nucleotide phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine; therefore, they reflect an inhibition of cAMP formation. In contrast, light had no effect on cAMP formation in photoreceptors of mutant mice, measured under identical conditions. Thus, elevated levels of cAMP in rds/rds retinas in vivo result from abnormalities in cAMP synthesis in the mutant photoreceptor cells. In addition to regulation by light, cAMP formation in photoreceptor cells is regulated by dopamine, acting through dopamine D4 receptors. A dopamine D2/D4 receptor agonist, quinpirole, reduced cAMP levels in dark-adapted normal retinas in vitro, but not in rds/rds retinas. Our data indicate that alterations in a signal transduction pathway that leads to inhibition of adenylyl cyclase might underlie the abnormalities in cAMP levels in mutant rds/rds retinas. Heterozygous rds/+ photoreceptors demonstrated a normal pattern of light-evoked and quinpirole-mediated down-regulation of cAMP. Thus, partial expression of the normal phenotype is sufficient to render normal characteristics of cAMP regulation to the photoreceptors of the heterozygous mouse. The data obtained in the present study might be relevant to the understanding of photoreceptor pathology of patients with peripherin/rds mutations.

Adenylyl Cyclases↗
PubMed2001

Transgenic Bcl-2 expressed in photoreceptor cells confers both death-sparing and death-inducing effects.

To examine its potential role within the retina as a modulator of cell death and photoreceptor degeneration, bcl-2 expression was targeted to the photoreceptors of transgenic mice by the human IRBP promoter. Three transgenic families were established, with levels of transgene expression between 0.2 and two-fold relative to that of endogenous bcl-2. The effect of bcl-2 expression on genetically programmed photoreceptor degeneration was evaluated by crossing these transgenic mice with mice that develop a rapid degeneration of rod photoreceptors due to expression of a distinct transgene, SV40 T antigen (Tag). Transgenic Bcl-2 was localized to photoreceptor inner segments and was capable of abrogating the activation of caspase activity and the resulting cell death associated with ectopic expression of Tag. However, Bcl-2 itself ultimately caused photoreceptor cell death and retinal degeneration. Several proteins not expressed normally in Tag or other transgenic retinas undergoing photoreceptor degeneration were induced in the Bcl-2 transgenic retinas. Analysis by mass spectroscopy identified one of these proteins as alphaA-crystallin, a member of a protein family that associates with cellular stress. Since Bcl-2 can promote as well as spare cell death in the same photoreceptor population, its potential utility in ameliorating photoreceptor death in human hereditary blinding disorders is compromised.

Animals↗
PubMed2002

Long term dietary supplementation with zeaxanthin reduces photoreceptor death in light-damaged Japanese quail.

The purpose of these studies was to evaluate the effects of light damage on Japanese quail whose retinal carotenoids had been experimentally manipulated through altered diets. The birds were raised 6 months on a commercial turkey diet (T), on a custom carotenoid-deficient diet (C-) containing 90% less carotenoid than the T diet, or on Z+ diet [the C- diet supplemented with natural zeaxanthin (35mgkg(-1) food)]. Equal numbers of males and females on each diet were exposed to nine intervals (1hr on, 2hr off) of 3200lux cool white light, then placed in the dark for 14hr before tissue collection. One retina was immediately frozen for HPLC analysis; the other eye was immediately fixed and processed for microscopy. There were no significant differences in the retinal carotenoid concentrations in hatch-mates that were and were not exposed to light. Supplementation resulted in three- to four-fold increases in retinal zeaxanthin and no change in retinal lutein or alpha-tocopherol, but the C- diet did not reduce the retinal carotenoid concentration in C- birds below that in T birds. The light-exposed retinas had significant numbers of apoptotic photoreceptors and photoreceptor ghosts. The number of ghosts was negatively correlated with the number of dying photoreceptors (P<0.05), and with retinal concentrations of zeaxanthin, alpha-tocopherol or gamma-tocopherol (P<0.04, 0.02, 0.04, respectively), but not with lutein. The number of dying photoreceptors was positively correlated with alpha-tocopherol and the sum alpha-tocopherol plus zeaxanthin (P<0.1; P0.04). Photoreceptor death was semi-quantitatively scored, assuming that ghosts were formed by removal of apoptotic photoreceptors with nuclear condensation. Stepwise regression produced a good model (r(2)=0.67;P <0.0001) for predicting death scores from retinal concentrations of zeaxanthin (Standard Coefficient=-0.76) and lutein (Standard Coefficients=+0.43). Absence of lutein in gender-specific analyses suggests lutein served as surrogate marker for gender. Combined analysis of the C- and T birds also demonstrated that dying photoreceptors were negatively correlated with retinal zeaxanthin. These data confirm our previous report that retinal carotenoids prevent photoreceptor cell death, and provide the first direct evidence that retinal zeaxanthin protects photoreceptors from light-induced death.

Age Factors↗
PubMed2002

Dopamine has a critical role in photoreceptor degeneration in the rd mouse.

Photoreceptors receive paracrine input from dopaminergic interplexiform cells. Rod photoreceptors in the rd mouse degenerate rapidly due to a specific gene defect. We investigated the effects of dopamine on rd mouse photoreceptors in retinal organ culture. Retinas were harvested from rd or wild-type mice at postnatal day 2 and grown in organ culture for 27 days. When antagonists for either D(1)- or D(2)-family dopamine receptors were added to the media, photoreceptor degeneration was blocked. Furthermore, when dopamine was depleted by the addition of 6-hydroxydopamine and pargyline, photoreceptor survival appeared comparable to wild-type retinal cultures. The addition of a dopamine agonist induced photoreceptor degeneration in dopamine-depleted rd organ cultures. In all cases, photoreceptors maintained robust staining of opsin. These results demonstrate that dopamine antagonists or dopamine depletion blocks photoreceptor degeneration and that dopamine is necessary for photoreceptor degeneration in the rd mouse retinal organ culture model, indicating that dopamine antagonists may represent a therapeutic strategy in retinal degenerative disease.

Animals↗
PubMed1990

Photoreceptor survival-promoting activity in interphotoreceptor matrix preparations: characterization and partial purification.

It is well established that many types of cells are dependent on trophic factors for their survival. We are investigating whether photoreceptor survival may also be dependent upon such a factor, as well as the possibility that the interphotoreceptor matrix (IPM), which lies between the outer retina and the RPE, may be a source of photoreceptor survival-promoting activities. Well-characterized cultures of embryonic chick retinal neurons and photoreceptors, in which the photoreceptors spontaneously degenerate between 7 and 10 days in culture, were used to test this hypothesis. Crude extracts of IPM were found to support three- to fourfold increases in photoreceptor survival in 10-day cultures. This response was dose-dependent, saturable, and specific for photoreceptors, since there was no difference in the number of non-photoreceptor neurons between treated and control cultures. This photoreceptor survival-promoting activity (PSPA) may function when present either as a substratum-bound molecule or as a medium supplement. PSPA is heat labile, sensitive to freeze-thawing, and stable only within a very narrow pH range. The activity binds to heparin affinity columns but, in contrast to the behavior of growth factors such as FGF, it can be eluted from the columns at low salt concentrations (0.5 M NaCl). PSPA is eluted from a Sephacryl S-200 gel filtration column in two regions with Mr = 400-450 kDa and 33 kDa, respectively. SDS-gel electrophoresis suggests that the high molecular weight activity is composed of aggregates of lower molecular weight molecules. While this factor has not been purified to homogeneity, the combination of heparin-agarose affinity chromatography and hydrophobic interaction chromatography on phenyl-Sepharose columns results in 720-fold purification of the activity, with one unit of PSPA activity corresponding to 40 ng protein. This partial purification is accompanied by substantial reduction in the complexity of protein patterns in silver-stained SDS-gels. These findings are potentially important since a macromolecular factor promoting photoreceptor survival could play a role in the normal development of the retina, and could also further our understanding of retinal degenerations such as retinitis pigmentosa.

Animals↗
PubMed1990

Proteoglycans in the mouse interphotoreceptor matrix. III. Changes during photoreceptor development and degeneration in the rds mutant.

The distribution of sulfated proteoglycans in the interphotoreceptor matrix (IPM) was examined during development and degeneration of photoreceptors in the rds mouse with electron microscopy after staining with the cationic dye Cupromeronic Blue (CmB). Three distinct CmB-positive filaments types were observed: type A (45-55 nm long and around 5 nm in diameter), type B (up to 0.5 micron long and 5-10 nm in diameter), and type C filaments (up to 1 micron long and 15-25 nm in diameter. During early postnatal development, before degenerative changes occur in photoreceptors, CmB-positive filaments were virtually identical in morphology and pattern of development as those recently reported for the normal mouse IPM (Tawara, Varner and Hollyfield, 1989, Exp. Eye Res. 48, 815-39). From 10 days to 1 year of age, during the period of progressive degeneration and loss of photoreceptor cells, numerous type B and type C filaments were present in the IPM. Type B filaments were distributed throughout the IPM, whereas type C were predominantly located around the apical termination of photoreceptor inner segments and between the pigment epithelial microvilli. Type A filaments were located principally in the apical cytoplasm of the pigment epithelial cells and in the proximal IPM. In the 20-month-old rds mouse, a time when virtually no photoreceptor cells remain, only minimal CmB staining was evident at the interface between the pigment epithelium and retina. Pretreatment with chondroitinase AC eliminated most CmB-positive filaments from the 18-day-old and 20-month-old mouse IPM. These findings suggest that there are no major differences in structural type or early postnatal development of chondroitin sulfate-type proteoglycans in the IPM between rds and normal mice. Any differences in distribution of chondroitin sulfate-type proteoglycans between rds and normal mice can be accounted for by the absence of photoreceptor outer segments and progressive loss of photoreceptor cells in this mutant. The disappearance of these IPM proteoglycans following photoreceptor degeneration suggests that photoreceptors may be critically involved in the maintenance of these matrix components.

Animals↗
PubMed1992

RPE conditioned medium stimulates photoreceptor cell survival, neurite outgrowth and differentiation in vitro.

In the present study we have investigated retinal pigment epithelium-photoreceptor cell interactions in vitro, and their contributions to photoreceptor cell survival and differentiation. Preparations enriched for intact photoreceptor cells from neonatal rat retina were grown in either serum-free medium supplemented with RPE-conditioned medium (RPE-CM) or in serum-free medium alone. A variety of substrate conditions were tested for the best neurite outgrowth. Cultures were monitored for 7 days by light and electron microscopy, as well as by opsin, vimentin and carbonic anhydrase-C immunocytochemistry. RPE-CM was found to stimulate both proliferation of flat cells and photoreceptor differentiation. The number of photoreceptors bearing neurites and their neurite length measurements showed significant differences between the RPE-CM group and the control group within 20 hr in culture. Elimination of contaminating flat cells by the addition of an antimitotic drug prevented photoreceptor cell morphological maturation; however, these cells survived as round cell bodies without processes for at least 10 days in the presence of RPE-CM and expressed opsin during this period. Conditioned medium from the flat-cell monolayers did not support photoreceptor differentiation or their survival. However, the presence of flat cells was a requisite to achieve any neurite outgrowth even in the presence of RPE-CM. In the absence of RPE-CM, neither photoreceptors nor flat cells survived or proliferated. Heat and trypsin treatment of the RPE-CM abolished all its growth-supporting activities which indicates its proteinaceous nature. This represents the first time in vitro that an RPE-derived factor(s) has been shown to be responsible for photoreceptor cell survival and differentiation.

Animals↗
PubMed2005

Photoreceptor layer features in eyes with closed macular holes: optical coherence tomography findings and correlation with visual outcomes.

PURPOSE: Study correlation between optical coherence tomography (OCT) findings and visual acuity (VA) outcomes after successful macular hole surgery (MHS). DESIGN: Retrospective cross-sectional study. METHODS: Postoperative OCT scans were analyzed in 34 eyes of 30 patients. Raw files of horizontal and vertical OCT scans were exported to Adobe Photoshop 7.0. Measured parameters included central foveal thickness, photoreceptor thickness, photoreceptor reflectivity, and relative reflectivity of photoreceptor to retinal pigment epithelium in the foveal area. Foveal configuration was subjectively graded. RESULTS: OCT scans were obtained at a median of 2 years (1 month to 10 years) postoperatively. The median visual acuity was 20/80 (20/50 to 8/200) preoperatively and 20/50 (20/20 to 5/200) postoperatively. The median foveal thickness was 198.5 micro (148 to 283). The mean (SD) photoreceptor layer thickness was 16.5 (8) micro in the 500 micro area and 17.5 (8) micro in the 1000 micro area. Mean (SD) of relative reflectivity of the photoreceptor layer was 0.60 (0.10) in both 500 micro and 1000 micro area. Postoperative VA did not correlate with foveal thickness or foveal configuration. Central (500 micro and 1000 micro) photoreceptor thickness was significantly correlated with final VA (r = .38, P = .026, each). Relative reflectivity of photoreceptors to retinal pigment epithelium in the 500 micro area was correlated with postoperative VA at a borderline significance (r = .32, P = .07). Relative reflectivity of photoreceptors to retinal pigment epithelium in the 1000 micro area was not significantly correlated with postoperative VA (r = .27, P = .12). CONCLUSION: Specific retinal features can be assessed from OCT images. Morphology and thickness of the foveal photoreceptor layer correlate well with macular function after successful MHS. Outer retinal features appear to be more important to determine postoperative visual function. Inner retinal features may be more relevant for the ophthalmoscopic appearance of anatomic closure.

Adult↗
PubMed2006

Targeted inactivation of synaptic HRG4 (UNC119) causes dysfunction in the distal photoreceptor and slow retinal degeneration, revealing a new function.

HRG4 (UNC119) is a photoreceptor protein predominantly localized to the photoreceptor synapses and to the inner segments to a lesser degree. A heterozygous truncation mutation in HRG4 was found in a patient with late onset cone-rod dystrophy, and a transgenic (TG) mouse expressing the identical mutant protein developed late onset retinal degeneration, confirming the pathogenic potential of HRG4. Recently, the dominant negative pathogenic mechanism in the TG model was shown to involve increased affinity of the truncated mutant HRG4 for its target, ARL2, which leads to a delayed decrease in its downstream target, mitochondrial ANT1, mitochondrial stress, synaptic degeneration, trans-synaptic degeneration, and whole photoreceptor degeneration by apoptosis. In this study, the mouse HRG4 (MRG4) gene was cloned and targeted to construct a knock-out (KO) mouse model of HRG4 in order to study the effects of completely inactivating this protein. The KO model was examined by genomic Southern blotting, Western blotting, immunofluorescence, funduscopy, LM and EM histopathology, ERG, and TUNEL analyses. The KO model developed a slowly progressive retinal degeneration, characterized by mottling in the fundus, mild thinning of the photoreceptor layer, and increase in apoptosis as early as 6 months, dramatic acceleration at approximately 17 months, and virtual obliteration of the photoreceptors by 20 months. When compared to retinal degeneration in the TG model, significant differences existed in the KO consisting of more severe and early photoreceptor death without evidence of early synaptic and trans-synaptic degeneration as seen in the TG, confirmed by LM and EM histopathology, ERG, and Western blotting of synaptic proteins. The results indicated a dysfunction in the KO outside the synapses in the distal end of photoreceptors where MRG4 is also localized. Differences in the phenotypes of retinal degeneration in the KO and TG models reflect a dysfunction in the two opposite ends of photoreceptors, i.e., the distal inner/outer segments and proximal synapses, respectively, indicating a second function of MRG4 in the distal photoreceptor and dual functionality of MRG4. Thus, inactivation of MRG4 by gene targeting resulted in a retinal degeneration phenotype quite different from that previously seen in the TG, attesting to the multiplicity of MRG4 function, in addition to the importance of this protein for normal retinal function. These models will be useful in elucidating the functions of HRG4/MRG4 and the mechanism of slow retinal degeneration.

Adaptor Proteins, Signal Transducing↗
PubMed1989

Opposing microtubule- and actin-dependent forces in the development and maintenance of structural polarity in retinal photoreceptors.

We have used embryonic cells grown in vitro to study the roles of microtubules and microfilaments in the development and maintenance of the polarized shape of retinal photoreceptors. After several days in culture, isolated cone photoreceptors displayed a highly elongated, compartmentalized morphology similar to that of photoreceptors in vivo. When treated with the microtubule-depolymerizing agent nocodazole, these elongated photoreceptors became progressively shorter, eventually losing their compartmentalized structure and becoming round. Conversely, treatment with the actin-depolymerizing agent cytochalasin D caused the elongated photoreceptors to lengthen even further. Computer-assisted, quantitative analysis showed that responses of individual cells to both nocodazole and Cytochalasin D were concentration-dependent, graded, and reversible. Immunocytochemical studies suggested the presence of longitudinally oriented actin filaments and microtubules in these photoreceptors, prominent in the region that undergoes the most pronounced length changes in response to cytoskeletal inhibitors. Prior to becoming elongated, photoreceptor precursors could be accurately identified in early retinal cultures. These round cells undergo a stereotyped sequence of morphogenetic transformations during in vitro development, including elongation and compartmentalization of the cell body as well as extension of a single neurite. Treatment with either cytochalasin D or nocodazole completely blocked morphogenesis. In addition, cytochalasin D caused the development of an abnormal, elongated cell process, which formed by a microtubule-dependent mechanism. These nocodazole and cytochalasin D effects also were reversible. Taken together, these data indicate that the complex developmental transformations leading to photoreceptor polarization occur in the absence of intercellular contacts, and are predominantly controlled by intracellular cytoskeletal forces. They suggest the existence of continuously active, oppositely directed, microtubule- and actin-dependent forces, the balance of which is a determining factor in the development as well as the maintenance of the elongated, compartmentalized organization of photoreceptor cells.

Actins↗
PubMed1989

Differential effects of excitatory amino acids on photoreceptors of the chick retina: an electron-microscopical study using the zinc-iodide-osmium technique.

Although excitotoxins derived from acidic amino acids are known to damage neurons in the inner nuclear and ganglion cell layers of the retina, little is known about their effects on photoreceptors. This study examines the acute and long-term effects of excitotoxins on photoreceptors of the chick retina. The zinc-iodide-osmium (ZIO) technique, which darkly labels a substantial subpopulation of synaptic vesicles in normal photoreceptor terminals, was used to supplement routine electron microscopy. Two-day-old chicks received a single intraocular injection of either 10, 50, or 200 nmoles kainic acid (KA), 200 nmoles N-methyl-D-aspartic acid (NMDA), or 200 nmoles quisqualic acid (QUIS), and were allowed to survive for either 6 h, 7 d, or 21 d. At 6 h, following exposure to 10, 50, and 200 nmoles KA, there was swelling and disruption of photoreceptor lamellae of the outer segments. At 7- and 21-d survival, 50 and 200 nmoles KA resulted in rounded, condensed synaptic terminals, which contained a high density of synaptic vesicles. However, there was complete loss of ZIO-positive vesicles within these photoreceptors. Outer segments were still disrupted, although small patches of lamellae were evident, suggestive of regeneration. Following exposure to QUIS, there was extensive swelling of outer segment lamellae at 6 h survival. Synaptic ribbons in terminals were also swollen. At longer survival periods, QUIS exposure resulted in a reduction of ZIO-positive vesicles, as well as swollen lamellae in outer segments. NMDA exposure, at either short or long-term survival, did not alter photoreceptor morphology, including the pattern of ZIO stain. The prolonged effects of KA, and to a lesser extent QUIS, on photoreceptors suggests that these drugs have a long-term effect on photoreceptor function. The ZIO technique provides a novel and potentially useful approach for identification of damaged photoreceptors.

Amino Acids↗
PubMed1990

Associative learning changes intrinsic to Hermissenda type A photoreceptors.

The eyes of the nudibranch mollusc Hermissenda have previously been shown to contain 2 classes of photoreceptors. Type B photoreceptors exhibit increased light responses and membrane excitability after repeated pairings of light and rotation and play an important role in the mediation of associatively produced reductions in phototactic behavior. Type A photoreceptors have also been shown to change with associative training. In previous research, Type A photoreceptors from trained animals were found to have reduced light responses. Because these recordings were obtained from synaptically intact cells, it was not possible to determine whether the effects of associative training reflected changes in synaptic input to Type A photoreceptors or intrinsic changes in somatic conductances. In the present study, intracellular recordings from synaptically isolated Type A photoreceptors were obtained on retention days after training, and pairing-specific decreases in light-induced generator potentials and decreases in resting input resistance were observed. Current- and voltage-clamp analysis of Type A photoreceptors from untrained animals revealed that an important determinant of the steady-state light response was a calcium-activated K+ current (IK-Ca). Thus, Type A photoreceptors also appear to be a primary site for associative information storage in Hermissenda. It is suggested that enhancement of IK-Ca by associative training may contribute to the diminished light response of Type A photoreceptors.

Accommodation, Ocular↗
PubMed1994

Atonal is the proneural gene for Drosophila photoreceptors.

The Drosophila peripheral nervous system comprises four major types of sensory element: external sense organs (such as mechano-sensory bristles), chordotonal organs (internal stretch receptors), multiple dendritic neurons, and photoreceptors. During development, the selection of neural precursors for external sense organs requires the proneural genes of the achaete-scute complex, which encode basic-helix-loop-helix transcription factors. These genes do not, however, control precursor selection for chordotonal organs or photoreceptors, raising the question of whether other proneural genes exist or a different mechanism of neurogenesis operates. Here we show that atonal (ato), originally isolated as a proneural gene for chordotonal organs, is also the proneural gene for photoreceptors. Pattern formation in the Drosophila eye involves a succession of cell fate specifications. Of the eight photoreceptors within each ommatidium of the compound eye, the photoreceptor R8 is the first to appear in the eye imaginal disc, right behind the morphogenetic furrow. The appearance of other photoreceptors (R1-7) follows in a defined sequence that is thought to arise by induction from R8 (refs 8, 9, 11, 12). We find that photoreceptor formation requires the function of atonal at the morphogenetic furrow and that atonal is specifically required for R8 selection. Formation of other photoreceptors does not directly require atonal function, but does depend on R8 selection by atonal. Thus, photoreceptors are selected by two mechanisms: R8 by a proneural mechanism, and R1-7 by local recruitment.

Animals↗
PubMed1999

Microglia increase as photoreceptors decrease in the aging avian retina.

PURPOSE: There is evidence that microglial activation occurs with normal aging in some regions of the brain of rodents. We investigated the pattern of microglia in the retinas of young and aged quail and pigeons to determine if age-related retinal changes evoked migration of microglia into the outer retina. In quail we also investigated the correlation between activated microglia and age-related photoreceptor loss. METHODS: Microglia were identified with the monoclonal antibody QH1 in cryosectioned eyes from pigeons, ages 2 to 20 years (n = 14), and in paraffin sections from six-month (n = 15) and one-year-old quail (n = 30). Rounded microglia in the photoreceptor layer were counted in consecutive 400x fields from temporal to nasal. Photoreceptor counts were made from 10 quail retina flat mounts. The photoreceptor number was compared to the number of microglia in corresponding regions of the same retina. RESULTS: Rounded microglia were detected among the photoreceptors of pigeons and quail. Significantly more of these microglia were found in peripheral than in central regions close to the pecten (pigeon p < 0.002 and quail p < 0.01). Furthermore, more microglial cells were present among peripheral photoreceptors of older quail (p < 0.03) and pigeons (p < 0.05) than in the younger birds. In the peripheral retina of the older quail, microglia were significantly and inversely related to the number of photoreceptors (r2 = 0.9; p < 0.001). CONCLUSIONS: Increased microglial were observed in the peripheral retina of both old quail and old pigeons. In the quail, the rounded (activated) microglia were distributed preferentially in regions of greatest photoreceptor loss. Microglial activation does not appear to be a general phenomenon of the aging retina, but in quail activation appears directly related to photoreceptor loss. It is unclear at this time how the change in microglia shape and distribution is related to their neuroprotective / neurotoxic potential.

Aging↗