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PubMed1983

Biogenesis of blowfly photoreceptor membranes is regulated by 11-cis-retinal.

Biogenesis of photoreceptor membranes has been investigated by analyzing the rhodopsin and opsin content of microvillar photoreceptor membranes after injecting retinal isomers and radioactive amino acids into the compound eyes of carotenoid-deficient blowflies. The amount of rhodopsin in the membranes was measured photometrically in extracts of isolated rhabdoms. The opsin content of the membranes and the level of radioactive labelling of opsin were measured after separating the membrane proteins by dodecyl sulphate/polyacrylamide gel electrophoresis. In the photoreceptor membrane of carotenoid-deficient flies the rhodopsin and opsin content is less than 4% of that in normal flies where opsin may constitute about 65% of the total membrane protein. In carotenoid-deficient flies the incorporation of rhodopsin into photoreceptor membranes is triggered by 11-cis-retinal but not all-trans retinal. After injection of 11-cis-retinal the opsin content of the photoreceptor membranes increases in parallel with the rhodopsin content. Radioactive labelling of opsin reveals that 11-cis-retinal triggers an incorporation of newly synthesized opsin into photoreceptor membranes whereas all-trans retinal does not induce the assembly of opsin into photoreceptor membranes. Light-dependent incorporation of radioactive labelled opsin into membranes with a high rhodopsin content shows that not only the visual pigment chromophore but also the opsin undergoes a light-dependent turnover. The findings raise the possibility that opsin synthesis in blowfly photoreceptors and consequently the assembly of photoreceptor membranes is regulated by 11-cis-retinal.

Animals↗
PubMed1997

Photoreceptor cells of the pike pineal organ as cellular circadian oscillators.

In the pike pineal, the rhythm of melatonin (MEL) secretion is driven by a population of cellular circadian oscillators, synchronized by the 24 h light/dark (LD) cycle. Because the pineal photoreceptor contains both the input and output pathways of the clock, this cell is likely to be a cellular circadian system by itself. To support this idea, we have dissociated and cultured pike pineal cells as well as purified photoreceptors. In culture, the pineal cells reassociated in follicles, surrounded by collagen fibres. At the electron microscopic level, they appeared well preserved. Total cells consisted mainly of photoreceptors and glia. Purified cells corresponded exclusively to photoreceptors. Under LD, MEL production was rhythmic. Under constant darkness (DD), the rhythm was well sustained for at least six 24 h cycles (tau = 24/27 h) with 1 x 10(6) total cells/well or below; with 2 x 10(6) total cells/well, a strong damping occurred towards high levels as soon as after the second cycle. At the density of 0.5 x 10(6) cells/well, purified photoreceptors produced less MEL than an equivalent amount of total cells. However, the pattern of the oscillations was similar to that observed with 2 x 10(6) total cells, i.e. a damping occurred rapidly. Decreasing the density to 0.125 x 10(6) photoreceptors/well resulted in a loss of homogeneity among replicates. The production of melatonin by single photoreceptors was monitored by means of the reverse haemolytic plaque assay. Both under LD and under DD, the number of photoreceptors releasing melatonin was higher during the (subjective) dark than during the (subjective) light. The results provide strong support to the idea that the pike pineal photoreceptor is a cellular circadian system. Expression of the oscillations seemed to depend on several factors, including cell to cell contacts between photoreceptors. There is indication that also MEL and glia might be involved.

Activity Cycles↗
PubMed1999

The localization of glutathione peroxidase in the photoreceptor cells and the retinal pigment epithelial cells of Wistar and Royal College of Surgeons dystrophic rats.

INTRODUCTION: If degenerating photoreceptor outer segments not phagocytized by RPE cells in the retina of Royal College Surgeons (RCS) rats were to undergo peroxidation, the distribution of glutathione peroxidase (GSH-PO) in the mitochondria or cytoplasm of the retina might be altered. We evaluated the immunocytochemical localization of GSH-PO to identify subcellular organelles in sections of the retinas of RCS rats. METHODS: Immunoblot analysis confirmed the presence of GSH-PO molecules in the retinas of RCS and Wistar rats aged 3 weeks. Sections were reacted with the F(ab) fragment of anti-rat alphaGSH-PO and then examined by laser scanning microscopy (LSM) and transmission electron microscopy (TEM). RESULTS: The size of the GSH-PO molecule in the retina was about 21 KD in the mitochondria and 23 KD in the cytosol in both strains of rats. LSM revealed fluorescent granules in the photoreceptor inner segments of the Wistar rats, and immunohistochemical TEM revealed GSH-PO in the mitochondria of their photoreceptor inner segments and retinal pigment epithelial (RPE) cells. In the RCS rats, the degenerating photoreceptor outer segments were clearly seen to be positive for anti-GSH-PO by conventional light microscopy (CLM). However, the photoreceptor inner segments of the RCS rats were negative for staining with anti-GSH-PO by LSM, and no GSH-PO could be detected in the mitochondria of the photoreceptor inner segments or RPE cells by immuno-TEM. CONCLUSION: Degeneration of the photoreceptor outer segments induced mitochondrial damage in the photoreceptor inner segments, and as a result GSH-PO shifted from the photoreceptor inner segments to the degenerating outer segments.

Animals↗
PubMed2005

Iris-derived cells from adult rodents and primates adopt photoreceptor-specific phenotypes.

PURPOSE: The purpose of this study was to investigate the effects of various genes related to photoreceptor development on rodent and primate iris cells and the potential of iris cells as donor cells for retinal transplantation. METHODS: Adult rat and monkey iris tissue were cultured in serum-free medium containing basic fibroblast growth factor. Gene deliveries of Crx, Nrl, NeuroD and some combinations (Crx-Nrl, Crx-NeuroD) were performed with recombinant retrovirus. Immunocytochemistry, Western blot analysis, RT-PCR, and intracellular recording were used to examine the expression of photoreceptor-specific phenotypes in the iris-derived cells after gene transfer, . Coculture of the iris-derived cells with embryonic retinal explant was conducted, to investigate the potential integration of these cells in coculture conditions. RESULTS: Misexpression of Crx induced adult rat iris cells to express several photoreceptor-specific antigens and transcripts, such as rhodopsin, recoverin, cGMP-gated channel, arrestin, interphotoreceptor retinal-binding protein, rhodopsin kinase, and NeuroD. In primates, a combination of Crx and NeuroD was needed to induce monkey iris-derived cells to adopt photoreceptor-specific phenotypes. Furthermore, the photoreceptor-like cells derived from both rat- and primate-iris tissues showed rod photoreceptor-specific electrophysiological response to light stimuli after Crx and Crx-NeuroD gene transfer, respectively. The results further showed that iris-derived cells integrated in the developing host retina in coculture conditions. CONCLUSIONS: Adult iris-derived cultured cells of both rodents and primates expressed photoreceptor-specific phenotypes by inductions of transcription factors. These iris-derived photoreceptor-like cells have electrophysiological characteristics of rod photoreceptors. Furthermore, they can integrate in the developing retina under coculture conditions.

Animals↗
PubMed2006

Analysis of kinesin-2 function in photoreceptor cells using synchronous Cre-loxP knockout of Kif3a with RHO-Cre.

PURPOSE: To determine the relationship between the presence of kinesin-2 and photoreceptor cell viability and opsin transport, by generating RHO-Cre transgenic mice and breeding them to mice with a floxed kinesin-2 motor gene. METHODS: Different lines of RHO-Cre transgenic mice were generated and characterized by transgene expression, histology, and electrophysiology. Mice from one line, showing uniform transgene expression, were crossed with Kif3a(flox)/Kif3a(flox) mice. The time courses of photoreceptor Cre expression, KIF3A loss, ectopic opsin accumulation, and photoreceptor cell death were determined by Western blot analysis and microscopy. RESULTS: One of the RHO-Cre lines effected synchronous expression of Cre and thus uniform excision of Kif3a(flox) in rod photoreceptors across the retina. After the neonatal production of CRE and the initiation of KIF3A loss, ectopic accumulation of opsin was detected by postnatal day (P)7, and ensuing photoreceptor cell death was evident after P10 and almost complete by P28. Of importance, the photoreceptor cilium formed normally, and the disc membranes of the nascent outer segment remained normal until P10. CONCLUSIONS: The RHO-Cre-8 mice provide an improved tool for studying gene ablation in rod photoreceptor cells. Regarding kinesin-2 function in photoreceptor cells, the relatively precise timing of events after CRE excision of Kif3a(flox) allows us to conclude that ectopic opsin is a primary cellular lesion of KIF3A loss, consistent with the hypothesis that opsin is a cargo of kinesin-2. Moreover, it demonstrates that KIF3A loss results in very rapid photoreceptor cell degeneration.

Animals↗
PubMed2006

Loss of BCL-XL in rod photoreceptors: Increased susceptibility to bright light stress.

PURPOSE: BCL-X(L), an anti-apoptotic member of the BCL-2 family proteins and a cell death/survival checkpoint regulator, was shown to be upregulated in bright light-stressed mouse photoreceptors during an investigation of bright light-induced protein expression. To investigate the significance of BCL-X(L) upregulation in the bright light damage model, the Bcl-x gene was disrupted specifically in mouse rod photoreceptors, and the effect of Bcl-x disruption was characterized on retinal apoptosis, function, and morphology. METHODS: Rod-specific Bcl-x knockout mice, generated by mating mouse opsin promoter-controlled Cre mice with floxed Bcl-x mice, were subjected to bright light stress. Retinal apoptosis in the bright light-stressed conditional Bcl-x knockout mice was characterized with TUNEL, DNA fragmentation, and nuclear staining assays. Photoreceptor structural and functional integrity in the bright light-stressed conditional Bcl-x knockout mice was determined by measuring photoreceptor outer nuclear layer (ONL) thickness and electroretinography amplitudes. RESULTS: Disruption of Bcl-x in rod photoreceptors caused increased photoreceptor apoptosis, decreased retinal function, and decreased ONL thickness in bright light-stressed mice. CONCLUSIONS: The loss of BCL-X(L) increased rod photoreceptor susceptibility to bright light stress. Although the biochemical mechanism(s) of BCL-X(L) in photoreceptor death or survival has not been investigated extensively, results of the present study suggest that BCL-X(L), a cell survival/death checkpoint regulator, is involved in photoreceptor survival under bright light stress.

Animals↗
PubMed2003

Neural images of pursuit targets in the photoreceptor arrays of male and female houseflies Musca domestica.

Male houseflies use a sex-specific frontal eye region, the lovespot, to detect and pursue mates. We recorded the electrical responses of photoreceptors to optical stimuli that simulate the signals received by a male or female photoreceptor as a conspecific passes through its field of view. We analysed the ability of male and female frontal photoreceptors to code conspecifics over the range of speeds and distances encountered during pursuit, and reconstructed the neural images of these targets in photoreceptor arrays. A male's lovespot photoreceptor detects a conspecific at twice the distance of a female photoreceptor, largely through better optics. This detection distance greatly exceeds those reported in previous behavioural studies. Lovespot photoreceptors respond more strongly than female photoreceptors to targets tracked during pursuit, with amplitudes reaching 25 mV. The male photoreceptor also has a faster response, exhibits a unique preference for stimuli of 20-30 ms duration that selects for conspecifics and deblurs moving images with response transients. White-noise analysis substantially underestimates these improvements. We conclude that in the lovespot, both optics and phototransduction are specialised to enhance and deblur the neural images of moving targets, and propose that analogous mechanisms may sharpen the neural image still further as it is transferred to visual interneurones.

Animals↗
PubMed2002

Dysfunctional light-evoked regulation of cAMP in photoreceptors and abnormal retinal adaptation in mice lacking dopamine D4 receptors.

Dopamine is a retinal neuromodulator that has been implicated in many aspects of retinal physiology. Photoreceptor cells express dopamine D4 receptors that regulate cAMP metabolism. To assess the effects of dopamine on photoreceptor physiology, we examined the morphology, electrophysiology, and regulation of cAMP metabolism in mice with targeted disruption of the dopamine D4 receptor gene. Photoreceptor morphology and outer segment disc shedding after light onset were normal in D4 knock-out (D4KO) mice. Quinpirole, a dopamine D2/D3/D4 receptor agonist, decreased cAMP synthesis in retinas of wild-type (WT) mice but not in retinas of D4KO mice. In WT retinas, the photoreceptors of which were functionally isolated by incubation in the presence of exogenous glutamate, light also suppressed cAMP synthesis. Despite the similar inhibition of cAMP synthesis, the effect of light is directly on the photoreceptors and independent of dopamine modulation, because it was unaffected by application of the D4 receptor antagonist l-745,870. Nevertheless, compared with WT retinas, basal cAMP formation was reduced in the photoreceptors of D4KO retinas, and light had no additional inhibitory effect. The results suggest that dopamine, via D4 receptors, normally modulates the cascade that couples light responses to adenylyl cyclase activity in photoreceptor cells, and the absence of this modulation results in dysfunction of the cascade. Dark-adapted electroretinogram (ERG) responses were normal in D4KO mice. However, ERG b-wave responses were greatly suppressed during both light adaptation and early stages of dark adaptation. Thus, the absence of D4 receptors affects adaptation, altering transmission of light responses from photoreceptors to inner retinal neurons. These findings indicate that dopamine D4 receptors normally play a major role in regulating photoreceptor cAMP metabolism and adaptive retinal responses to changing environmental illumination.

Adaptation, Ocular↗
PubMed2002

[Morphologic changes in photoreceptor connecting cilia in experimental phototoxic retinopathy].

PURPOSE: It has been suggested that structural alterations of the photoreceptor connecting cilium are a primary defects leading to photoreceptor degeneration in some forms of inherited retinal degenerations (5). In a series of 17 eyes with retinitis pigmentosa (RP) and with various genetic forms of RP, examined by electron microscopy, no structural abnormalities were found in the arrangement of the ciliary microtubules. However, a 10% reduction in the ciliary diameter was recorded in RP photoreceptors (12). The question arose: is thinning of the cilium a primary defect associated with RP, or a secondary abnormality related to degenerative processes in photoreceptors irrespective of the cause? The aim of this study was to examine the photoreceptor connecting cilia in the early stages of experimental light induced retinal degeneration in the rat, by conducting a structural and morphometric survey of the relevant electron-micrographs. In addition, the effects of various fixation techniques on the ciliary structure were compared. MATERIAL AND METHOD: Analysis of 124 transmission electron micrographs of 9 controls and 155 transmission electron micrographs of 55 light damaged animals was conducted. For the effects of fixation on morphometry 72 transmission electron micrographs from an additional 4 controls (43 negatives) and 8 light damaged animals (29 negatives) were examined. Light damage was induced by exposure to 1000 lux of white light for 120 minutes. Retinal samples were fixed either in 2.5% glutaraldehyde or by high pressure freezing followed by freeze-substitution. RESULTS: This study showed that one of the early morphological alterations occurring in rat photoreceptors damaged by light is a reduction of ciliary diameter of approximately 10%. It was not associated with any apparent ultrastructural changes in the axoneme. It was also found that the degree of ciliary shrinkage largely depends on the fixation technique used. Cryo-fixation followed by freeze substitution shows more shrinkage than chemical fixation by immersion in glutaraldehyde. CONCLUSIONS: It is suggested, that reduction in photoreceptor cilium diameter is a secondary and non-specific change. It is not a unique phenomenon, observed not only in human photoreceptors, which are undergoing degeneration in RP. It can be induced in otherwise healthy rat retina, in which photoreceptor degeneration was caused by exposure to toxic levels of light.

Animals↗
PubMed2003

Growth of the postnatal rat retina in vitro: quantitative RT-PCR analyses of mRNA expression for photoreceptor proteins.

PURPOSE: To investigate whether previously reported changes in protein expression of middle and long (M/L) and short (S) wavelength cone opsin pigments in cultured retina are correlated with changes in their gene expression. Additionally, to elucidate the importance of a functional retinal pigment epithelium for the development of photoreceptor outer segments. METHODS: Neonatal rat retinas were maintained in culture for 11 days and either fixed in 4% paraformaldehyde for immunohistochemistry or prepared for RNA extraction, reverse transcription polymerase chain reaction (RT-PCR), and quantitative RT-PCR. S-cone and M/L-cone photoreceptors as well as rod photoreceptors were immunohistochemically identified using specific antibodies. Peanut agglutinin (PNA)-lectin histochemistry was used to identify interphotoreceptor matrix associated with cone photoreceptors. Immunolabeling for ED-1 and RPE65 was performed in combination with PNA-lectin staining to examine interactions between photoreceptor cells and the retinal pigment epithelium. Relative estimates of mRNA expression levels for M/L-opsin, S-opsin, recoverin, and rhodopsin in normal and cultured retina were determined by using quantitative RT-PCR. RESULTS: Strong immunolabeling for recoverin and rhodopsin accumulated in outer segments as well as photoreceptor somata in vitro. Cultured and normal retinas showed similar relative expression levels of recoverin and rhodopsin mRNA. In cultured rat retina, the density of S-cones was high and M/L-cones could not be immunohistochemically detected. However, M/L-cone photoreceptor mRNA was detectable, but at a fourfold lower level in cultured than in vivo retinas. The S-cone photoreceptor mRNA level was almost twofold lower than in vivo. Retinal pigment epithelium cells in cultured specimens showed no RPE65 immunolabeling, but expressed immunolabeling for ED-1 indicating phagocytic activity of these cells in vitro. CONCLUSIONS: We assume that the high density of S-cones and virtually no M/L-cones seen in in vitro retinas might represent an immature stage with numerous S-cones and suppressed transdifferentiation into M/L-cone phenotype. A non-functional relationship between photoreceptor cells and a dysfunctional retinal pigment epithelium may have severe consequences for the development of outer segments.

Animals↗
PubMed1992

Basic fibroblast growth factor and local injury protect photoreceptors from light damage in the rat.

Injection of basic fibroblast growth factor (bFGF) into the eye, intravitreally or subretinally, delays photoreceptor degeneration in inherited retinal dystrophy in the rat, as does local injury to the retina (Faktorovich et al., 1990). To determine whether this heparin-binding peptide or local injury is effective in any other form of photoreceptor degeneration, we examined their protective roles in light damage. Albino rats of the F344 strain were exposed to 1 or 2 weeks of constant fluorescent light (115-200 footcandles), either with or without 1 microliter of bFGF solution (1150 ng/microliters in PBS) injected intravitreally or subretinally 2 d before the start of light exposure. Uninjected and intravitreally PBS-injected controls showed the loss of a majority of photoreceptor nuclei and the loss of most inner and outer segments after 1 week of light exposure, while intravitreal injection of bFGF resulted in significant photoreceptor rescue. The outer nuclear layer in bFGF-injected eyes was two to three times thicker than in controls, and the inner and outer segments showed a much greater degree of integrity. Following recovery in cyclic light for 10 d after 1 week of constant light exposure, bFGF-injected eyes showed much greater regeneration of photoreceptor inner and outer segments than did the controls. bFGF also increased the incidence of presumptive macrophages, located predominantly in the inner retina, but the evidence suggests they are not directly involved in photoreceptor rescue. Subretinal injection of bFGF resulted in photoreceptor rescue throughout most of the superior hemisphere in which the injection was made, with rescue extending into the inferior hemisphere in many of the eyes. Remarkably, the insertion of a dry needle or injection of PBS into the subretinal space also resulted in widespread photoreceptor rescue, extending through 70% or more of the superior hemisphere, and sometimes into the inferior hemispheres. This implicates the release and widespread diffusion of some endogenous survival-promoting factor from the site of injury in the retina. Our findings indicate that the photoreceptor rescue activity of bFGF is not restricted to inherited retinal dystrophy in the rat, and that light damage is an excellent model for studying the cellular site(s), kinetics, and molecular mechanisms of both the normal function of bFGF and its survival-promoting activity. Moreover, the injury-related rescue suggests that survival-promoting factors are readily available to provide a protective role in case of injury to the retina, presumably comparable to those that mediate the "conditioning lesion" effect in other neuronal systems.

Animals↗
PubMed1988

Aspartate separation of the scotopic threshold response (STR) from the photoreceptor a-wave of the cat and monkey ERG.

We recorded ERG responses at the cornea of cat and monkey and identified the initial negative wave elicited by very dim stimuli as the scotopic threshold response (STR) comparable to that previously recognized by intraretinal recordings of cat. The STR, but not the photoreceptor a-wave, was eliminated by intravitreal aspartate in both cat and monkey, which demonstrated that the STR origin was post-photoreceptoral. Intraretinal recordings before and after aspartate confirmed that the a-wave of cat with bright light was fast-PIII from photoreceptors, and further showed that there was minimal or no extracellular activity recordable near the photoreceptors with very dim stimuli after aspartate. This study showed practical ways to separate the STR from the photoreceptor a-wave in corneal records, by the range of stimulus intensity (STR with dim stimuli; photoreceptor a-wave with bright stimuli) and by response latency (STR, long latency; photoreceptor a-wave, short latency). These recordings provide the first evidence that the monkey has an STR, and that it is post-photoreceptoral like the STR of cat. Further, this provides support to consider that the corneal negative STR wave of the human ERG with dim light may also be post-photoreceptoral.

Action Potentials↗
PubMed1994

Long-term photoreceptor transplants in dystrophic and normal mouse retina.

PURPOSE: To determine the long-term status of transgenic photoreceptors transplanted to the subretinal space of both rd mutant (receptorless) and normal mouse retina. METHODS: Microaggregates of neural retina from transgenic mice containing lacZ-labeled photoreceptors were transplanted to the subretinal space of adult rd mutant and normal mice. The transplant site was examined by light and electron microscopy at monthly intervals up to 9 months after transplantation surgery. RESULTS: Photoreceptors develop and survive well if transplanted with the proper orientation to the retinal pigment epithelium (RPE). The status of the photoreceptors, including outer segments and synaptic terminals, appear normal for at least 9 months after transplantation; they continue to express the lacZ reporter gene. Cones survive as well as rods. Transplants to the normal mouse develop normally, whereas the host photoreceptors displaced from the RPE degenerate. A barrier, formed by Müller cell processes, develops after photoreceptor degeneration in both normal and rd mouse retina and demarcates host from transplant tissue. Areas can be found in which neural processes have penetrated this barrier. There is no evidence of host-graft rejection. CONCLUSION: Transplanted progenitor photoreceptors develop and survive well for long periods of time in either the rd mutant or normal retina if they are properly positioned. In the former, they reconstitute a photoreceptor layer; in the latter, they replace the host photoreceptor layer, which degenerates after being displaced from the RPE. Areas of potential contact between donor and host neurons exist in these transplants.

Animals↗
PubMed1996

Development and maintenance of outer segments by isolated chick embryo photoreceptor cells in culture.

PURPOSE: To investigate the capacity of isolated chick embryo photoreceptors to develop and maintain outer-segment processes in dissociated cell cultures, in the absence of pigment epithelial and glial cells. METHODS: Cells were obtained from the retinas of embryonic day (ED) 17 chick embryos, after the onset of outer-segment formation in vivo. After 5 to 12-minute incubation in Ca++ and Mg++-free Hank's balanced salt solution, neural retinas were freed from other optical tissues, including the pigment epithelium. Retinal cell suspensions were prepared by repeated pipetting after mild trypsinization and were grown in serum-containing medium on a polyornithine-coated substratum. Cell differentiation was evaluated using phase-contrast and transmission electron microscopes and by autoradiographic analysis of the uptake of putative amino acid neurotransmitters, lectin cytochemical analysis, and immunocytochemical analysis with rod and cone-specific antibodies. Cells isolated from ED 8 retinas, before the onset of outer-segment formation in vivo, were also studied. RESULTS: At culture onset, ED 17 cells appeared morphologically undifferentiated and devoid of processes; differentiated features could be detected after 24 to 48 hours in vitro. Photoreceptor cells were the most abundant cell type after 6 days in vitro, followed by nonphotoreceptor multipolar neurons and morphologically undifferentiated cells. Autoradiographic analysis showed extensive Na+ -dependent uptake of (2,3,4-(3)H)gamma- aminobutyric acid in nonphotoreceptor neurons, whereas photoreceptors were labeled predominantly with 3H-glutamate. Most of the photoreceptors were labeled with fluorescent peanut lectin and with a sheep polyclonal antibody against bovine rhodopsin. Subsets of photoreceptors, on the other hand, were immunoreactive with cone- or rod-specific monoclonal antibodies COS-1, OS-2, 50-1B11, or Rho-4D2. Approximately 50% to 65% of the photoreceptors positive with these monoclonal antibodies showed a remarkable polarization of immunoreactive materials, which accumulated predominantly, or even exclusively, in an outer-segment-like apical process. When viewed on the transmission electron microscope, these outer-segment-like processes appeared as distal expansions of the photoreceptor cilium and contained disc-like membranous profiles. Outer-segment-like processes also could be detected using the electron microscope and by immunocytochemical analysis of cultures of ED 8 retinal cells. CONCLUSIONS: After undergoing morphologic dedifferentiation as a result of tissue dissociation, isolated retinal photoreceptors, grown in the absence of contact-mediated cell interactions and of pigment epithelial and glial cells, can regenerate and maintain a highly polarized pattern of structural and molecular organization, including the formation of outer-segment-like processes. The cultures provide an experimental system for the investigation of cellular and molecular mechanisms regulating further development and maturation of these photoreceptor structures.

Animals↗
PubMed2005

Characterization of a transgenic mouse line lacking photoreceptor development within the ventral retina.

A unique transgenic mouse line was generated by incorporating a minigene that contained a cone-specific human cone transducin alpha-subunit (GNAT2) promoter, an attenuated diphtheria toxin A (DTA) gene, and an enhancer element from human interphotoreceptor retinoid-binding protein (IRBP) gene. This transgenic mouse line is designated h-GNAT2pro-DTA. During postnatal retinal development, both transgenic and non-transgenic retinas showed similar morphology and thickness at P1. Between ages P8 and P30, all retinal layers became recognizable in non-transgenic and also in transgenic dorsal retinas. However, in the ventral retina of the transgenic mice the photoreceptor layers did not develop. This aberration occurred as a result of abnormal cellular development, rather than as a consequence of retinal degeneration. In adult transgenic animals, approximately 44% of the retina located dorsally appeared morphologically normal, whereas 32% of the retina located ventrally was completely lacking photoreceptor development. The 24% mid-retinal region exhibited transitional morphology containing malformed photoreceptors. At P360 or older, the thickness of retina layers was reduced in both dorsal and ventral regions. The abnormality observed in transgenic retinas involved mainly the photoreceptors; the other retinal cell types were all present in both dorsal and ventral retinas. Since the DTA gene was only expressed in cone cells, the absence of cone photoreceptors in the transgenic retina was to be expected. However, what was unexpected was the concomitant absence of rod photoreceptors in the ventral retina, suggesting that the presence of cones may be important for the development of rods. This new transgenic line can lead to better understanding of photoreceptor development, and may serve as a new animal model for studying photoreceptor-related retinal diseases.

Animals↗
PubMed2003

The expression of the Leber congenital amaurosis protein AIPL1 coincides with rod and cone photoreceptor development.

PURPOSE: The Leber congenital amaurosis (LCA) protein AIPL1 is present only in the rod photoreceptors of the adult human retina and is excluded from the cone photoreceptors. LCA, however, is characterized by an absence of both rod and cone function at birth or shortly thereafter. Therefore, this study was conducted to determine whether AIPL1 is present in the rod and cone photoreceptors of the developing human retina. In addition, the expression of NUB1, a putative AIPL1-interacting partner, was examined. METHODS: A comprehensive spatiotemporal examination of AIPL1 distribution during development was performed by immunohistochemistry, using a previously characterized AIPL1 anti-serum. Immunofluorescence confocal microscopy was used to examine the coexpression of AIPL1 with the long/medium (L/M) and short (S) wavelength-sensitive cone photoreceptors in the developing human retina. The spatiotemporal distribution of NUB1 was also examined by immunohistochemistry, using a newly developed anti-serum to the C terminus of NUB1. RESULTS: AIPL1 protein was detected by 11.8 fetal weeks in the central fetal human retina. With continued development, AIPL1 expression spread gradually toward peripheral retina. AIPL1 was expressed in the L/M and S cone photoreceptors in addition to the rods of the developing human retina. NUB1 was localized in cell nuclei throughout the human fetal and adult eye at all time points. CONCLUSIONS: The pattern of AIPL1 expression closely follows the centroperipheral gradient in photoreceptor development. The data suggest that AIPL1 is essential for the normal development of both rod and cone photoreceptor cells and that mutations in the AIPL1 gene cause the death or dysfunction of photoreceptors early in development resulting in blindness or severely impaired vision at birth.

Adaptor Proteins, Signal Transducing↗
PubMed1995

Apoptotic photoreceptor cell death after traumatic retinal detachment in humans.

OBJECTIVE: To determine the mechanism of photoreceptor cell death after traumatic retinal detachment in humans. DESIGN: Clinical records from 1975 to 1993 of 75 patients, whose eyes were enucleated after traumatic retinal detachment, were reviewed for age, sex, previous ocular or systemic medical history, interval from initial trauma to enucleation, visual acuity, and types of trauma. The patients were divided into five groups of 15 cases each, based on the interval from initial trauma to enucleation. The retinal tissue was examined for two markers of apoptosis: (1) nicked nuclear DNA in situ by the terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labeling (TUNEL) technique and (2) apoptotic bodies by light and electron microscopy. RESULTS: Of the 75 cases of ruptured globe and traumatic retinal detachment that were evaluated, 19 eyes (25.3%) showed TUNEL-positive labeling of photoreceptor cells. Nicked nuclear DNA was detected in photoreceptor cells of detached retinas as early as 8 hours after trauma. The detached retinas in seven of 15 eyes enucleated within 2 days after ocular trauma showed TUNEL-positive photoreceptor nuclei. The number of cases showing TUNEL-positive photoreceptor nuclei decreased as the interval between initial trauma and enucleation increased. The TUNEL-positive photoreceptor cells could still be seen in the detached retinas of two eyes enucleated 22 days after trauma. Light microscopy disclosed condensation and fragmentation of photoreceptor nuclei in the detached retinas. Electron microscopy showed structures resembling apoptotic bodies phagocytosed by neighboring cells in the TUNEL-positive retinas. CONCLUSIONS: Apoptosis is an important mechanism of photoreceptor cell degeneration in the early stage after traumatic retinal detachment in humans.

Adolescent↗
PubMed1999

Extraretinal photoreceptors at the compound eye's posterior margin in Drosophila melanogaster.

Many invertebrates have supplementary extraocular photoreceptors that often are implicated in circadian rhythms. An extraretinal group of candidate photoreceptors in the fruit fly, Drosophila melanogaster, has been revealed previously at the posterior margin of the compound eye by using a photoreceptor-specific monoclonal antibody (Hofbauer and Buchner [1989] Naturwissen 76:335-336), but it never has been characterized. Here, we report the fine structure of this cell cluster reported by Hofbauer and Buchner, which is called "eyelet," as well as the further candidacy of their visual pigment and neurotransmitter. Eyelet forms a specialized, pigmented organ with cells that have numerous microvilli arranged into coherent rhabdomeres. The presence of rhabdomeric microvilli is a defining feature of a photoreceptor, reported here for the first time in eyelet. The rhabdomeres exhibit Rh6 opsin-like immunoreactivity, which provides evidence that the photoreceptors are functional: they fail to immunostain with antibodies against NINAE (Rh1), Rh4, or Rh5. The photoreceptors have been shown previously to exhibit histamine-like immunoreactivity, but they also stain with a monoclonal antiserum raised against Drosophila choline acetyltransferase (ChAT), suggesting that the photoreceptors not only may contain histamine but also can synthesize acetylcholine. A ChAT-immunoreactive axon bundle originating from eyelet terminates in the cortex of the anterior medulla. This bundle also is seen with reduced silver stains. Electron microscopic examination revealed four axon profiles of similar size in this bundle, indicating that eyelet contains at least four photoreceptors. The pathway of eyelet's axon bundle coincides with the precocious pathway of Bolwig's nerve that arises from the larval organ of sight. The origin and possible function of eyelet are discussed.

Animals↗