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1
LINBERG, KENNETH A., TSUTOMU SAKAI, GEOFFREY P. LEWIS, and STEVEN K. FISHER. "Experimental retinal detachment in the cone-dominant ground squirrel retina: Morphology and basic immunocytochemistry." Visual Neuroscience 19, no. 5 (September 2002): 603–19. http://dx.doi.org/10.1017/s095252380219506x.
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The cellular responses of the cone-dominant ground squirrel retina to retinal detachment were examined and compared to those in rod-dominant species. Retinal detachments were made in California ground squirrels. The retinas were prepared for light, electron, and confocal microscopy. Tissue sections were labeled with antibodies to cone opsins, rod opsin, glial fibrillary acidic protein (GFAP), vimentin, synaptophysin, cytochrome oxidase, and calbindin D 28K. Wax sections were probed with the MIB-1 antibody to detect proliferating cells. By 10 h postdetachment many photoreceptor cells in the ground squirrel already show structural signs of apoptosis. At 1 day many photoreceptors have collapsed inner segments (IS), yet others still have short stacks of outer segment discs. At 3 days there is a marked increase in the number of dying photoreceptors. Rod and medium-/long-wavelength opsins are redistributed in the cell membrane to their synaptic terminals. At 7 days photoreceptor cell death has slowed. Some regions of the outer nuclear layer (ONL) have few photoreceptor somata. IS remnants are rare on surviving photoreceptors. At 28 days these trends are even more dramatic. Retinal pigmented epithelium (RPE) cells do not expand into the subretinal space. The outer limiting membrane (OLM) appears flat and uninterrupted. Müller cells remain remarkably unreactive; they show essentially no proliferation, only negligible hypertrophy, and there is no increase in their expression of GFAP or vimentin. Horizontal cells show no dendritic sprouting in response to detachment. The speed and extent of photoreceptor degeneration in response to detachment is greater in ground squirrel than in cat retina—only a small number of rods and cones survive at 28 days of detachment. Moreover, the almost total lack of Müller cell and RPE reactivity in the ground squirrel retina is a significant difference from results in other species.
2
Bok, Dean. "Cell biology of retinal photoreceptors and pigment epithelium." Proceedings, annual meeting, Electron Microscopy Society of America 47 (August 6, 1989): 794–95. http://dx.doi.org/10.1017/s0424820100155943.
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Retinal photoreceptors (rods and cones) and retinal pigment epithelium (RPE) are highly-polarized cells that reside in close association within the eye. They carry out their interactions from a time early in embryologic life until the demise of the organism. RPE cells position their basal surfaces on an elaborate membrane (Bruch's membrane) which is intercalated between this epithelial monolayer and the photoreceptor blood supply. Their apical surfaces face the light-sensitive organelles (outer segments) of the photoreceptors. Interactions between photoreceptors and RPE take place at this interface.Mechanisms underlying photoreceptor phototransduction are now understood to a significant degree. When a photon is absorbed by a rod or cone photopigment, its chromophore, 11-cis retinaldehyde (11-cis retinal), isomerizes to the all trans form (t-retinol) and the protein undergoes a conformational change as well. The latter event activates a retina-specific GTPase (a G-protein called transducin) which, in turn, activates a retina-specific cGMP phosphodiesterase (cGMP-PDE). This cGMP-PDE then reduces the intracellular levels of cGMP which results in the closure of Na+/Ca++ channels in the photoreceptor outer segment plasma membrane. The cell hyperpolarizes as a result and release of neurotransmitter at the synaptic terminal is diminished.
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Ozaki, Ema, Luke Gibbons, Nuno GB Neto, Paul Kenna, Michael Carty, Marian Humphries, Pete Humphries, et al. "SARM1 deficiency promotes rod and cone photoreceptor cell survival in a model of retinal degeneration." Life Science Alliance 3, no. 5 (April 20, 2020): e201900618. http://dx.doi.org/10.26508/lsa.201900618.
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Retinal degeneration is the leading cause of incurable blindness worldwide and is characterised by progressive loss of light-sensing photoreceptors in the neural retina. SARM1 is known for its role in axonal degeneration, but a role for SARM1 in photoreceptor cell degeneration has not been reported. SARM1 is known to mediate neuronal cell degeneration through depletion of essential metabolite NAD and induction of energy crisis. Here, we demonstrate that SARM1 is expressed in photoreceptors, and using retinal tissue explant, we confirm that activation of SARM1 causes destruction of NAD pools in the photoreceptor layer. Through generation of rho−/−sarm1−/− double knockout mice, we demonstrate that genetic deletion of SARM1 promotes both rod and cone photoreceptor cell survival in the rhodopsin knockout (rho−/−) mouse model of photoreceptor degeneration. Finally, we demonstrate that SARM1 deficiency preserves cone visual function in the surviving photoreceptors when assayed by electroretinography. Overall, our data indicate that endogenous SARM1 has the capacity to consume NAD in photoreceptor cells and identifies a previously unappreciated role for SARM1-dependent cell death in photoreceptor cell degeneration.
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Baden, T., and D. Osorio. "The Retinal Basis of Vertebrate Color Vision." Annual Review of Vision Science 5, no. 1 (September 15, 2019): 177–200. http://dx.doi.org/10.1146/annurev-vision-091718-014926.
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The jawless fish that were ancestral to all living vertebrates had four spectral cone types that were probably served by chromatic-opponent retinal circuits. Subsequent evolution of photoreceptor spectral sensitivities is documented for many vertebrate lineages, giving insight into the ecological adaptation of color vision. Beyond the photoreceptors, retinal color processing is best understood in mammals, especially the blueONsystem, which opposes short- against long-wavelength receptor responses. For other vertebrates that often have three or four types of cone pigment, new findings from zebrafish are extending older work on teleost fish and reptiles to reveal rich color circuitry. Here, horizontal cells establish diverse and complex spectral responses even in photoreceptor outputs. Cone-selective connections to bipolar cells then set up color-opponent synaptic layers in the inner retina, which lead to a large variety of color-opponent channels for transmission to the brain via retinal ganglion cells.
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Larison, K. D., and R. Bremiller. "Early onset of phenotype and cell patterning in the embryonic zebrafish retina." Development 109, no. 3 (July 1, 1990): 567–76. http://dx.doi.org/10.1242/dev.109.3.567.
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The regular arrangement of retinal cone cells in a mosaic pattern is a common feature of teleosts. In the zebrafish, Brachydanio rerio, the retinal cone mosaic comprises parallel rows consisting of a repeating motif of four cone types. In order to elucidate the temporal and spatial aspects of the genesis of the cone mosaic in the developing retina, we generated a monoclonal antibody that specifically binds to the double cone photoreceptor of the adult. We first saw staining in the developing retina with this antibody, FRet 43, at 48 hours postfertilization, the time at which the first photoreceptor cells undergo their final mitotic division. We then injected embryonic fish with the thymidine analog, 5-bromo-2′-deoxyuridine (BrdU), confirming with a double-labeling experiment that the onset of FRet 43 antigenicity occurs within three hours of the cellular division that generates the double cone photoreceptors. Then we stained tangential sections of the 54-hour embryonic retina with FRet 43, further showing that cells devoid of staining alternate with stained pairs of cells in a pattern that is consistent with the arrangement of photoreceptors in the adult cone mosaic. These results indicate that a marker of the double cone phenotype is expressed at approximately the same time as cellular birthday and that the mosaic patterning is present within 6 hours of this expression.
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BARNARD, ALUN R., JOANNE M. APPLEFORD, SUMATHI SEKARAN, KRISHNA CHINTHAPALLI, AARON JENKINS, MATHEAS SEELIGER, MARTIN BIEL, et al. "Residual photosensitivity in mice lacking both rod opsin and cone photoreceptor cyclic nucleotide gated channel 3 α subunit." Visual Neuroscience 21, no. 5 (September 2004): 675–83. http://dx.doi.org/10.1017/s0952523804215024.
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The mammalian retina contains three classes of photoreceptor. In addition to the rods and cones, a subset of retinal ganglion cells that express the putative sensory photopigment melanopsin are intrinsically photosensitive. Functional and anatomical studies suggest that these inner retinal photoreceptors provide light information for a number of non-image-forming light responses including photoentrainment of the circadian clock and the pupil light reflex. Here, we employ a newly developed mouse model bearing lesions of both rod and cone phototransduction cascades (Rho−/−Cnga3−/−) to further examine the function of these non-rod non-cone photoreceptors. Calcium imaging confirms the presence of inner retinal photoreceptors inRho−/−Cnga3−/−mice. Moreover, these animals retain a pupil light reflex, photoentrainment, and light induction of the immediate early genec-fosin the suprachiasmatic nuclei, consistent with previous findings that pupillary and circadian responses can employ inner retinal photoreceptors.Rho−/−Cnga3−/−mice also show a light-dependent increase in the number of FOS-positive cells in both the ganglion cell and (particularly) inner nuclear layers of the retina. The average number of cells affected is several times greater than the number of melanopsin-positive cells in the mouse retina, suggesting functional intercellular connections from these inner retinal photoreceptors within the retina. Finally, however, while we show that wild types exhibit an increase in heart rate upon light exposure, this response is absent inRho−/−Cnga3−/−mice. Thus, it seems that non-rod non-cone photoreceptors can drive many, but not all, non-image-forming light responses.
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Jaroszynska, Natalia, Philippa Harding, and Mariya Moosajee. "Metabolism in the Zebrafish Retina." Journal of Developmental Biology 9, no. 1 (March 15, 2021): 10. http://dx.doi.org/10.3390/jdb9010010.
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Retinal photoreceptors are amongst the most metabolically active cells in the body, consuming more glucose as a metabolic substrate than even the brain. This ensures that there is sufficient energy to establish and maintain photoreceptor functions during and after their differentiation. Such high dependence on glucose metabolism is conserved across vertebrates, including zebrafish from early larval through to adult retinal stages. As the zebrafish retina develops rapidly, reaching an adult-like structure by 72 hours post fertilisation, zebrafish larvae can be used to study metabolism not only during retinogenesis, but also in functionally mature retinae. The interplay between rod and cone photoreceptors and the neighbouring retinal pigment epithelium (RPE) cells establishes a metabolic ecosystem that provides essential control of their individual functions, overall maintaining healthy vision. The RPE facilitates efficient supply of glucose from the choroidal vasculature to the photoreceptors, which produce metabolic products that in turn fuel RPE metabolism. Many inherited retinal diseases (IRDs) result in photoreceptor degeneration, either directly arising from photoreceptor-specific mutations or secondary to RPE loss, leading to sight loss. Evidence from a number of vertebrate studies suggests that the imbalance of the metabolic ecosystem in the outer retina contributes to metabolic failure and disease pathogenesis. The use of larval zebrafish mutants with disease-specific mutations that mirror those seen in human patients allows us to uncover mechanisms of such dysregulation and disease pathology with progression from embryonic to adult stages, as well as providing a means of testing novel therapeutic approaches.
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Irie, Shoichi, Rikako Sanuki, Yuki Muranishi, Kimiko Kato, Taro Chaya, and Takahisa Furukawa. "Rax Homeoprotein Regulates Photoreceptor Cell Maturation and Survival in Association with Crx in the Postnatal Mouse Retina." Molecular and Cellular Biology 35, no. 15 (May 18, 2015): 2583–96. http://dx.doi.org/10.1128/mcb.00048-15.
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TheRaxhomeobox gene plays essential roles in multiple processes of vertebrate retina development. Many vertebrate species possessRaxandRax2genes, and different functions have been suggested. In contrast, mice contain a singleRaxgene, and its functional roles in late retinal development are still unclear. To clarify mouse Rax function in postnatal photoreceptor development and maintenance, we generated conditional knockout mice in whichRaxin maturing or mature photoreceptor cells was inactivated by tamoxifen treatment (RaxiCKO mice). WhenRaxwas inactivated in postnatalRaxiCKO mice, developing photoreceptor cells showed a significant decrease in the level of the expression of rod and cone photoreceptor genes and mature adult photoreceptors exhibited a specific decrease in cone cell numbers. In luciferase assays, we found that Rax and Crx cooperatively transactivateRhodopsinandcone opsinpromoters and that an optimum Rax expression level to transactivate photoreceptor gene expression exists. Furthermore, Rax and Crx colocalized in maturing photoreceptor cells, and their coimmunoprecipitation was observed in cultured cells. Taken together, these results suggest that Rax plays essential roles in the maturation of both cones and rods and in the survival of cones by regulating photoreceptor gene expression with Crx in the postnatal mouse retina.
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HANZLICEK, BRETT W., NEAL S. PEACHEY, CHRISTIAN GRIMM, STEPHANIE A. HAGSTROM, and SHERRY L. BALL. "Probing inner retinal circuits in the rod pathway: A comparison of c-fos activation in mutant mice." Visual Neuroscience 21, no. 6 (November 2004): 873–81. http://dx.doi.org/10.1017/s0952523804216078.
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We have used wild-type mice and mice possessing defects in specific retinal circuits in order to more clearly define functional circuits of the inner retina. The retina of the nob mouse lacks communication between photoreceptors and depolarizing bipolar cells (DBCs). Thus, all light driven activity in the nob mouse is mediated via remaining hyperpolarizing bipolar cell (HBC) circuits. Transducin null (Trα−/−) mice lack rod photoreceptor activity and thus remaining retinal circuits are solely generated via cone photoreceptor activity. Activation in inner retinal circuits in each of these mice was identified by monitoring light-induced expression of an immediate early gene, c-fos. The number of cells expressing c-fos in the inner retina was dependent upon stimulus intensity and was altered in a systematic fashion in mice with known retinal mutations. To determine whether c-fos is activated via circuits other than photoreceptors in the outer retina, we examined c-fos expression in tulp1−/− mice that lack photoreceptors in the outer retina; these mice showed virtually no c-fos activity following light exposure. Double-labeling immunohistochemical studies were carried out to more clearly define the population of c-fos expressing amacrine cells. Our results indicate that c-fos may be used to map functional circuits in the retina.
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Simões, Bruno F., Filipa L. Sampaio, Ellis R. Loew, Kate L. Sanders, Robert N. Fisher, Nathan S. Hart, David M. Hunt, Julian C. Partridge, and David J. Gower. "Multiple rod–cone and cone–rod photoreceptor transmutations in snakes: evidence from visual opsin gene expression." Proceedings of the Royal Society B: Biological Sciences 283, no. 1823 (January 27, 2016): 20152624. http://dx.doi.org/10.1098/rspb.2015.2624.
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In 1934, Gordon Walls forwarded his radical theory of retinal photoreceptor ‘transmutation’. This proposed that rods and cones used for scotopic and photopic vision, respectively, were not fixed but could evolve into each other via a series of morphologically distinguishable intermediates. Walls' prime evidence came from series of diurnal and nocturnal geckos and snakes that appeared to have pure-cone or pure-rod retinas (in forms that Walls believed evolved from ancestors with the reverse complement) or which possessed intermediate photoreceptor cells. Walls was limited in testing his theory because the precise identity of visual pigments present in photoreceptors was then unknown. Subsequent molecular research has hitherto neglected this topic but presents new opportunities. We identify three visual opsin genes, rh1 , sws1 and lws , in retinal mRNA of an ecologically and taxonomically diverse sample of snakes central to Walls' theory. We conclude that photoreceptors with superficially rod- or cone-like morphology are not limited to containing scotopic or photopic opsins, respectively. Walls' theory is essentially correct, and more research is needed to identify the patterns, processes and functional implications of transmutation. Future research will help to clarify the fundamental properties and physiology of photoreceptors adapted to function in different light levels.
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Slembrouck-Brec, Amélie, Amélie Rodrigues, Oriane Rabesandratana, Giuliana Gagliardi, Céline Nanteau, Stéphane Fouquet, Gilles Thuret, Sacha Reichman, Gael Orieux, and Olivier Goureau. "Reprogramming of Adult Retinal Müller Glial Cells into Human-Induced Pluripotent Stem Cells as an Efficient Source of Retinal Cells." Stem Cells International 2019 (July 15, 2019): 1–13. http://dx.doi.org/10.1155/2019/7858796.
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The reprogramming of human somatic cells to induced pluripotent stem cells (iPSCs) has broad applications in regenerative medicine. The generation of self-organized retinal structures from these iPSCs offers the opportunity to study retinal development and model-specific retinal disease with patient-specific iPSCs and provides the basis for cell replacement strategies. In this study, we demonstrated that the major type of glial cells of the human retina, Müller cells, can be reprogrammed into iPSCs that acquire classical signature of pluripotent stem cells. These Müller glial cell-derived iPSCs were able to differentiate toward retinal fate and generate concomitantly retinal pigmented epithelial cells and self-forming retinal organoid structures containing retinal progenitor cells. Retinal organoids recapitulated retinal neurogenesis with differentiation of retinal progenitor cells into all retinal cell types in a sequential overlapping order. With a modified retinal maturation protocol characterized by the presence of serum and high glucose levels, our study revealed that the retinal organoids contained pseudolaminated neural retina with important features reminiscent of mature photoreceptors, both rod and cone subtypes. This advanced maturation of photoreceptors not only supports the possibility to use 3D retinal organoids for studying photoreceptor development but also offers a novel opportunity for disease modeling, particularly for inherited retinal diseases.
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Choi, Hannah, Lei Zhang, Mark S. Cembrowski, Carl F. Sabottke, Alexander L. Markowitz, Daniel A. Butts, William L. Kath, Joshua H. Singer, and Hermann Riecke. "Intrinsic bursting of AII amacrine cells underlies oscillations in the rd1 mouse retina." Journal of Neurophysiology 112, no. 6 (September 15, 2014): 1491–504. http://dx.doi.org/10.1152/jn.00437.2014.
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In many forms of retinal degeneration, photoreceptors die but inner retinal circuits remain intact. In the rd1 mouse, an established model for blinding retinal diseases, spontaneous activity in the coupled network of AII amacrine and ON cone bipolar cells leads to rhythmic bursting of ganglion cells. Since such activity could impair retinal and/or cortical responses to restored photoreceptor function, understanding its nature is important for developing treatments of retinal pathologies. Here we analyzed a compartmental model of the wild-type mouse AII amacrine cell to predict that the cell's intrinsic membrane properties, specifically, interacting fast Na and slow, M-type K conductances, would allow its membrane potential to oscillate when light-evoked excitatory synaptic inputs were withdrawn following photoreceptor degeneration. We tested and confirmed this hypothesis experimentally by recording from AIIs in a slice preparation of rd1 retina. Additionally, recordings from ganglion cells in a whole mount preparation of rd1 retina demonstrated that activity in AIIs was propagated unchanged to elicit bursts of action potentials in ganglion cells. We conclude that oscillations are not an emergent property of a degenerated retinal network. Rather, they arise largely from the intrinsic properties of a single retinal interneuron, the AII amacrine cell.
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Hassall, Mark, Michelle McClements, Alun Barnard, Maria Patrício, Sher Aslam, and Robert Maclaren. "Analysis of Early Cone Dysfunction in an In Vivo Model of Rod-Cone Dystrophy." International Journal of Molecular Sciences 21, no. 17 (August 22, 2020): 6055. http://dx.doi.org/10.3390/ijms21176055.
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Retinitis pigmentosa (RP) is a generic term for a group of genetic diseases characterized by loss of rod and cone photoreceptor cells. Although the genetic causes of RP frequently only affect the rod photoreceptor cells, cone photoreceptors become stressed in the absence of rods and undergo a secondary degeneration. Changes in the gene expression profile of cone photoreceptor cells are likely to occur prior to observable physiological changes. To this end, we sought to achieve greater understanding of the changes in cone photoreceptor cells early in the degeneration process of the Rho−/− mouse model. To account for gene expression changes attributed to loss of cone photoreceptor cells, we normalized PCR in the remaining number of cones to a cone cell reporter (OPN1-GFP). Gene expression profiles of key components involved in the cone phototransduction cascade were correlated with tests of retinal cone function prior to cell loss. A significant downregulation of the photoreceptor transcription factor Crx was observed, which preceded a significant downregulation in cone opsin transcripts that coincided with declining cone function. Our data add to the growing understanding of molecular changes that occur prior to cone dysfunction in a model of rod-cone dystrophy. It is of interest that gene supplementation of CRX by adeno-associated viral vector delivery prior to cone cell loss did not prevent cone photoreceptor degeneration in this mouse model.
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Voigt, Andrew P., Nathaniel K. Mullin, S. Scott Whitmore, Adam P. DeLuca, Erin R. Burnight, Xiuying Liu, Budd A. Tucker, Todd E. Scheetz, Edwin M. Stone, and Robert F. Mullins. "Human photoreceptor cells from different macular subregions have distinct transcriptional profiles." Human Molecular Genetics 30, no. 16 (May 20, 2021): 1543–58. http://dx.doi.org/10.1093/hmg/ddab140.
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Abstract The human neural retina is a light sensitive tissue with remarkable spatial and cellular organization. Compared with the periphery, the central retina contains more densely packed cone photoreceptor cells with unique morphologies and synaptic wiring. Some regions of the central retina exhibit selective degeneration or preservation in response to retinal disease and the basis for this variation is unknown. In this study, we used both bulk and single-cell RNA sequencing to compare gene expression within concentric regions of the central retina. We identified unique gene expression patterns of foveal cone photoreceptor cells, including many foveal-enriched transcription factors. In addition, we found that the genes RORB1, PPFIA1 and KCNAB2 are differentially spliced in the foveal, parafoveal and macular regions. These results provide a highly detailed spatial characterization of the retinal transcriptome and highlight unique molecular features of different retinal regions.
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Kim, Sangbae, Albert Lowe, Rachayata Dharmat, Seunghoon Lee, Leah A. Owen, Jun Wang, Akbar Shakoor, et al. "Generation, transcriptome profiling, and functional validation of cone-rich human retinal organoids." Proceedings of the National Academy of Sciences 116, no. 22 (May 9, 2019): 10824–33. http://dx.doi.org/10.1073/pnas.1901572116.
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Rod and cone photoreceptors are light-sensing cells in the human retina. Rods are dominant in the peripheral retina, whereas cones are enriched in the macula, which is responsible for central vision and visual acuity. Macular degenerations affect vision the most and are currently incurable. Here we report the generation, transcriptome profiling, and functional validation of cone-rich human retinal organoids differentiated from hESCs using an improved retinal differentiation system. Induced by extracellular matrix, aggregates of hESCs formed single-lumen cysts composed of epithelial cells with anterior neuroectodermal/ectodermal fates, including retinal cell fate. Then, the cysts were en bloc-passaged, attached to culture surface, and grew, forming colonies in which retinal progenitor cell patches were found. Following gentle cell detachment, retinal progenitor cells self-assembled into retinal epithelium—retinal organoid—that differentiated into stratified cone-rich retinal tissue in agitated cultures. Electron microscopy revealed differentiating outer segments of photoreceptor cells. Bulk RNA-sequencing profiling of time-course retinal organoids demonstrated that retinal differentiation in vitro recapitulated in vivo retinogenesis in temporal expression of cell differentiation markers and retinal disease genes, as well as in mRNA alternative splicing. Single-cell RNA-sequencing profiling of 8-mo retinal organoids identified cone and rod cell clusters and confirmed the cone enrichment initially revealed by quantitative microscopy. Notably, cones from retinal organoids and human macula had similar single-cell transcriptomes, and so did rods. Cones in retinal organoids exhibited electrophysiological functions. Collectively, we have established cone-rich retinal organoids and a reference of transcriptomes that are valuable resources for retinal studies.
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MITCHELL, CHERYL K., BO HUANG, and DIANNA A. REDBURN-JOHNSON. "GABAA receptor immunoreactivity is transiently expressed in the developing outer retina." Visual Neuroscience 16, no. 6 (November 1999): 1083–88. http://dx.doi.org/10.1017/s0952523899166082.
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Extensive evidence has suggested a trophic role of γ-aminobutyric acid (GABA) on developing cone photoreceptors in postnatal retina. In a previous study, we showed that GABA raises intracellular calcium levels in the developing cones via activation of GABAA receptors. Using confocal microscopy in conjunction with immunocytochemistry, we have now demonstrated that (1) GABAA receptor subunits are localized on cone cell bodies as well as on cone pedicles, indicating that GABA has a direct, rather than indirect, effect on cones and (2) the temporal expression of GABAA receptor subunits coincides with the developmental effects of GABA on cone synaptogenesis. An antibody against the β 2/3 subunits of the GABAA receptor and a specific cone marker peanut-agglutinin lectin (PNA) were used to double-label wholemount neonatal retinal preparations. Results show that GABAA receptors are transiently expressed on cone photoreceptors in the early stages of postnatal retinal development. GABAA receptor immunoreactivity is clearly present on cone cell bodies and their processes and on other—as yet unidentified—elements (horizontal cells?) in the outer plexiform layer. Immunoreactivity decreases within cone photoreceptor somata after postnatal day 5, but persists in the processes of the outer plexiform layer until day 7. Our results provide support for the hypothesis that GABA acts as an important developmental regulator of cone photoreceptor maturation.
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Jin, Jing, Gregor J. Jones, and M. Carter Cornwall. "Movement of retinal along cone and rod photoreceptors." Visual Neuroscience 11, no. 2 (March 1994): 389–99. http://dx.doi.org/10.1017/s0952523800001735.
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AbstractSingle isolated photoreceptors can be taken through a visual cycle of light adaptation by bleaching visual pigment, followed by dark adaptation when supplied with 11–cis retinal. Light adaptation after bleaching is manifested by faster response kinetics and a permanent reduction in sensitivity to light flashes, presumed to be due to the presence of bleached visual pigment. The recovery of flash sensitivity during dark adaptation is assumed to be due to regeneration of visual pigment to pre-bleach levels. In previous work, the outer segments of bleached, light-adapted cells were exposed to 11–cis retinal. In the present work, the cell bodies of bleached photoreceptors were exposed. We report a marked difference between rods and cones. Bleached cones recover sensitivity when their cell bodies are exposed to 11–cis retinal. Bleached rods do not. These results imply that retinal can move freely along the cone photoreceptor, but retinal either is not taken up by the rod cell body or retinal cannot move from the rod cell body to the rod outer segment. The free transfer of retinal along cone but not along rod photoreceptors could explain why, during dark adaptation in the retina, cones have access to a store of 11–cis retinal which is not available to rods. Additional experiments investigated the movement of retinal along bleached rod outer segments. The results indicate that retinal can move along the rod outer segment, but that this movement is slow, occurring at about the same rate as the regeneration of visual pigment.
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Rajala, Ammaji, Feng He, Robert E. Anderson, Theodore G. Wensel, and Raju V. S. Rajala. "Loss of Class III Phosphoinositide 3-Kinase Vps34 Results in Cone Degeneration." Biology 9, no. 11 (November 7, 2020): 384. http://dx.doi.org/10.3390/biology9110384.
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The major pathway for the production of the low-abundance membrane lipid phosphatidylinositol 3-phosphate (PI(3)P) synthesis is catalyzed by class III phosphoinositide 3-kinase (PI3K) Vps34. The absence of Vps34 was previously found to disrupt autophagy and other membrane-trafficking pathways in some sensory neurons, but the roles of phosphatidylinositol 3-phosphate and Vps34 in cone photoreceptor cells have not previously been explored. We found that the deletion of Vps34 in neighboring rods in mouse retina did not disrupt cone function up to 8 weeks after birth, despite diminished rod function. Immunoblotting and lipid analysis of cones isolated from the cone-dominant retinas of the neural retina leucine zipper gene knockout mice revealed that both PI(3)P and Vps34 protein are present in mouse cones. To determine whether Vps34 and PI(3)P are important for cone function, we conditionally deleted Vps34 in cone photoreceptor cells of the mouse retina. Overall retinal morphology and rod function appeared to be unaffected. However, the loss of Vps34 in cones resulted in the loss of structure and function. There was a substantial reduction throughout the retina in the number of cones staining for M-opsin, S-opsin, cone arrestin, and peanut agglutinin, revealing degeneration of cones. These studies indicate that class III PI3K, and presumably PI(3)P, play essential roles in cone photoreceptor cell function and survival.
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Haley, Tammie L., Roland Pochet, Larry Baizer, Miriam D. Burton, John W. Crabb, Marc Parmentier, and Arthur S. Polans. "Calbindin D-28K immunoreactivity of human cone cells varies with retinal position." Visual Neuroscience 12, no. 2 (March 1995): 301–7. http://dx.doi.org/10.1017/s0952523800007987.
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AbstractCalbindin D-28K is a calcium-binding protein found in the cone but not rod photoreceptor cells in the retinas of a variety of species. Recent studies of the monkey retina indicated that calbindin D-28K may be expressed preferentially in non-foveal regions of the retina. In the current studies of human retinas, immunohistochemical experiments demonstrated that calbindin D-28K is reduced or absent in the fovea and parafovea, but prevalent in the perifovea and periphery. These findings were supported by the quantification of calbindin D-28K in 1-mm trephine punches obtained from different regions of the human retina. The specificity of the anti-calbindin D-28K antibodies used in these studies was confirmed by Western blot analysis using purified calbindin D-28K. The protein was purified from retinal tissue and its identity confirmed by partial amino-acid sequence analysis. The expression of calbindin D-28K did not correlate with the spectral properties of the cones, rather to their position in the retina. The study of spatially expressed genes, like the one encoding calbindin D-28K, may help explain the patterns of retinal degeneration seen in some human cone-rod dystrophies.
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HAIDER, NEENA B., PAUL DEMARCO, ARNE M. NYSTUEN, XIAONA HUANG, RICHARD S. SMITH, MAUREEN A. MCCALL, JÜRGEN K. NAGGERT, and PATSY M. NISHINA. "The transcription factorNr2e3functions in retinal progenitors to suppress cone cell generation." Visual Neuroscience 23, no. 6 (November 2006): 917–29. http://dx.doi.org/10.1017/s095252380623027x.
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The transcription factorNr2e3is an essential component for development and specification of rod and cone photoreceptors; however, the mechanism through which it acts is not well understood. In this study, we useNr2e3rd7/rd7mice that harbor a mutation inNr2e3, to serve as a model for the human retinal disease Enhanced S Cone Syndrome. Our studies reveal that NR2E3 is expressed in late retinal progenitors and differentiating photoreceptors of the developing retina and localized to the cell bodies of mature rods and cones. In particular, we demonstrate that the abnormal increase in cone photoreceptors observed inNr2e3rd7/rd7mice arise from ectopic mitotic progenitor cells that are present in the outer nuclear layer of the matureNr2e3rd7/rd7retina. A prolonged phase of proliferation is observed followed by abnormal retinal lamination with fragmented and disorganized photoreceptor synapses that result in a progressive loss of rod and cone function. An extended and pronounced wave of apoptosis is also detected at P30 and temporally correlates with the phase of prolonged proliferation. Approximately twice as many apoptotic cells were detected compared to proliferating cells. This wave of apoptosis appears to affect both rod and cone cells and thus may account for the concurrent loss of rod and cone function. We further show thatNr2e3rd7/rd7cones do not express rod specific genes andNr2e3rd7/rd7rods do not express cone specific genes. Our studies suggest that, based on its temporal and spatial expression, NR2E3 acts simultaneously in different cell types: in late mitotic progenitors, newly differentiating post mitotic cells, and mature rods and cones. In particular, this study reveals the function of NR2E3 in mitotic progenitors is to repress the cone generation program. NR2E3 is thus one of the few genes known to influence the competency of retinal progenitors while simultaneously directing the rod and cone differentiation.
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Shirai, Hiroshi, Michiko Mandai, Keizo Matsushita, Atsushi Kuwahara, Shigenobu Yonemura, Tokushige Nakano, Juthaporn Assawachananont, et al. "Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration." Proceedings of the National Academy of Sciences 113, no. 1 (December 22, 2015): E81—E90. http://dx.doi.org/10.1073/pnas.1512590113.
Full textAbstract:
Retinal transplantation therapy for retinitis pigmentosa is increasingly of interest due to accumulating evidence of transplantation efficacy from animal studies and development of techniques for the differentiation of human embryonic stem cells (hESCs) and induced pluripotent stem cells into retinal tissues or cells. In this study, we aimed to assess the potential clinical utility of hESC-derived retinal tissues (hESC-retina) using newly developed primate models of retinal degeneration to obtain preparatory information regarding the potential clinical utility of these hESC-retinas in transplantation therapy. hESC-retinas were first transplanted subretinally into nude rats with or without retinal degeneration to confirm their competency as a graft to mature to form highly specified outer segment structure and to integrate after transplantation. Two focal selective photoreceptor degeneration models were then developed in monkeys by subretinal injection of cobalt chloride or 577-nm optically pumped semiconductor laser photocoagulation. The utility of the developed models and a practicality of visual acuity test developed for monkeys were evaluated. Finally, feasibility of hESC-retina transplantation was assessed in the developed monkey models under practical surgical procedure and postoperational examinations. Grafted hESC-retina was observed differentiating into a range of retinal cell types, including rod and cone photoreceptors that developed structured outer nuclear layers after transplantation. Further, immunohistochemical analyses suggested the formation of host–graft synaptic connections. The findings of this study demonstrate the clinical feasibility of hESC-retina transplantation and provide the practical tools for the optimization of transplantation strategies for future clinical applications.
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HELVIK, JON V., ØYVIND DRIVENES, TORE H. NÆSS, ANDERS FJOSE, and HEE-CHAN SEO. "Molecular cloning and characterization of five opsin genes from the marine flatfish Atlantic halibut (Hippoglossus hippoglossus)." Visual Neuroscience 18, no. 5 (September 2001): 767–80. http://dx.doi.org/10.1017/s095252380118510x.
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Most molecular studies on the visual system in fish have been performed on freshwater teleosts such as goldfish and zebrafish where cones and rods appear simultaneously. Many marine fishes have long larval phase in the upper pelagic zone before transformation into a juvenile and a benthic life style. The retina at the larval stages consists of only single cone cells; later during metamorphosis double cones and rods develop. The flatfish Atlantic halibut (Hippoglossus hippoglossus) is a typical example of a marine species with such a two-step retina development. In this study, we have cloned five different opsins from Atlantic halibut larvae and juvenile retinas. Sequence comparisons with other opsins and phylogenetic analysis show that the five genes belong to the opsins of long-wavelength sensitive (L); middle-wavelength sensitive, MCone and MRod; and short-wavelength sensitive, SBlue and SUltraviolet, respectively. In situ hybridization analysis reveals expression in double cone (L and MCone), single cone (SBlue and SUltraviolet), and rod (MRod) types of photoreceptor cells in juvenile halibut retina. The visual system in Atlantic halibut seems therefore to have all four types of cone photoreceptors in addition to rod photoreceptors. This work shows for the first time molecular isolation of a complete set of retinal visual pigment genes from a marine teleost and describes the first cloning of an ultraviolet-sensitive opsin type from a marine teleost.
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Kevany, Brian M., and Krzysztof Palczewski. "Phagocytosis of Retinal Rod and Cone Photoreceptors." Physiology 25, no. 1 (February 2010): 8–15. http://dx.doi.org/10.1152/physiol.00038.2009.
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Photoreceptor cells maintain a roughly constant length by continuously generating new outer segments from their base while simultaneously releasing mature outer segments engulfed by the retinal pigment epithelium (RPE). Thus postmitotic RPE cells phagocytose an immense amount of material over a lifetime, disposing of photoreceptor cell waste while retaining useful content. This review focuses on current knowledge of outer segment phagocytosis, discussing the steps involved along with their critical participants as well as how various perturbations in outer segment (OS) disposal can lead to retinopathies.
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Hargrove-Grimes, Passley, Anupam K. Mondal, Jessica Gumerson, Jacob Nellissery, Angel M. Aponte, Linn Gieser, Haohua Qian, et al. "Loss of endocytosis-associated RabGEF1 causes aberrant morphogenesis and altered autophagy in photoreceptors leading to retinal degeneration." PLOS Genetics 16, no. 12 (December 23, 2020): e1009259. http://dx.doi.org/10.1371/journal.pgen.1009259.
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Rab-GTPases and associated effectors mediate cargo transport through the endomembrane system of eukaryotic cells, regulating key processes such as membrane turnover, signal transduction, protein recycling and degradation. Using developmental transcriptome data, we identified Rabgef1 (encoding the protein RabGEF1 or Rabex-5) as the only gene associated with Rab GTPases that exhibited strong concordance with retinal photoreceptor differentiation. Loss of Rabgef1 in mice (Rabgef1-/-) resulted in defects specifically of photoreceptor morphology and almost complete loss of both rod and cone function as early as eye opening; however, aberrant outer segment formation could only partly account for visual function deficits. RabGEF1 protein in retinal photoreceptors interacts with Rabaptin-5, and RabGEF1 absence leads to reduction of early endosomes consistent with studies in other mammalian cells and tissues. Electron microscopy analyses reveal abnormal accumulation of macromolecular aggregates in autophagosome-like vacuoles and enhanced immunostaining for LC3A/B and p62 in Rabgef1-/- photoreceptors, consistent with compromised autophagy. Transcriptome analysis of the developing Rabgef1-/- retina reveals altered expression of 2469 genes related to multiple pathways including phototransduction, mitochondria, oxidative stress and endocytosis, suggesting an early trajectory of photoreceptor cell death. Our results implicate an essential role of the RabGEF1-modulated endocytic and autophagic pathways in photoreceptor differentiation and homeostasis. We propose that RabGEF1 and associated components are potential candidates for syndromic traits that include a retinopathy phenotype.
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Tomita, Yohei, Chenxi Qiu, Edward Bull, William Allen, Yumi Kotoda, Saswata Talukdar, Lois E. H. Smith, and Zhongjie Fu. "Müller glial responses compensate for degenerating photoreceptors in retinitis pigmentosa." Experimental & Molecular Medicine 53, no. 11 (November 2021): 1748–58. http://dx.doi.org/10.1038/s12276-021-00693-w.
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AbstractPhotoreceptor degeneration caused by genetic defects leads to retinitis pigmentosa, a rare disease typically diagnosed in adolescents and young adults. In most cases, rod loss occurs first, followed by cone loss as well as altered function in cells connected to photoreceptors directly or indirectly. There remains a gap in our understanding of retinal cellular responses to photoreceptor abnormalities. Here, we utilized single-cell transcriptomics to investigate cellular responses in each major retinal cell type in retinitis pigmentosa model (P23H) mice vs. wild-type littermate mice. We found a significant decrease in the expression of genes associated with phototransduction, the inner/outer segment, photoreceptor cell cilium, and photoreceptor development in both rod and cone clusters, in line with the structural changes seen with immunohistochemistry. Accompanying this loss was a significant decrease in the expression of genes involved in metabolic pathways and energy production in both rods and cones. We found that in the Müller glia/astrocyte cluster, there was a significant increase in gene expression in pathways involving photoreceptor maintenance, while concomitant decreases were observed in rods and cones. Additionally, the expression of genes involved in mitochondrial localization and transport was increased in the Müller glia/astrocyte cluster. The Müller glial compensatory increase in the expression of genes downregulated in photoreceptors suggests that Müller glia adapt their transcriptome to support photoreceptors and could be thought of as general therapeutic targets to protect against retinal degeneration.
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Zhang, Furu, Kazuhiro Kurokawa, Ayoub Lassoued, James A. Crowell, and Donald T. Miller. "Cone photoreceptor classification in the living human eye from photostimulation-induced phase dynamics." Proceedings of the National Academy of Sciences 116, no. 16 (April 3, 2019): 7951–56. http://dx.doi.org/10.1073/pnas.1816360116.
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Human color vision is achieved by mixing neural signals from cone photoreceptors sensitive to different wavelengths of light. The spatial arrangement and proportion of these spectral types in the retina set fundamental limits on color perception, and abnormal or missing types are responsible for color vision loss. Imaging provides the most direct and quantitative means to study these photoreceptor properties at the cellular scale in the living human retina, but remains challenging. Current methods rely on retinal densitometry to distinguish cone types, a prohibitively slow process. Here, we show that photostimulation-induced optical phase changes occur in cone cells and carry substantial information about spectral type, enabling cones to be differentiated with unprecedented accuracy and efficiency. Moreover, these phase dynamics arise from physiological activity occurring on dramatically different timescales (from milliseconds to seconds) inside the cone outer segment, thus exposing the phototransduction cascade and subsequent downstream effects. We captured these dynamics in cones of subjects with normal color vision and a deuteranope, and at different macular locations by: (i) marrying adaptive optics to phase-sensitive optical coherence tomography to avoid optical blurring of the eye, (ii) acquiring images at high speed that samples phase dynamics at up to 3 KHz, and (iii) localizing phase changes to the cone outer segment, where photoactivation occurs. Our method should have broad appeal for color vision applications in which the underlying neural processing of photoreceptors is sought and for investigations of retinal diseases that affect cone function.
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Allocca, Mariacarmela, Claudio Mussolino, Maria Garcia-Hoyos, Daniela Sanges, Carolina Iodice, Marco Petrillo, Luk H. Vandenberghe, et al. "Novel Adeno-Associated Virus Serotypes Efficiently Transduce Murine Photoreceptors." Journal of Virology 81, no. 20 (August 15, 2007): 11372–80. http://dx.doi.org/10.1128/jvi.01327-07.
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ABSTRACT Severe inherited retinal diseases, such as retinitis pigmentosa and Leber congenital amaurosis, are caused by mutations in genes preferentially expressed in photoreceptors. While adeno-associated virus (AAV)-mediated gene transfer can correct retinal pigment epithelium (RPE) defects in animal models, approaches for the correction of photoreceptor-specific diseases are less efficient. We evaluated the ability of novel AAV serotypes (AAV2/7, AAV2/8, AAV2/9, AAV2rh.43, AAV2rh.64R1, and AAV2hu.29R) in combination with constitutive or photoreceptor-specific promoters to improve photoreceptor transduction, a limiting step in photoreceptor rescue. Based on a qualitative analysis, all AAV serotypes tested efficiently transduce the RPE as well as rod and cone photoreceptors after subretinal administration in mice. Interestingly, AAV2/9 efficiently transduces Müller cells. To compare photoreceptor transduction from different AAVs and promoters in both a qualitative and quantitative manner, we designed a strategy based on the use of a bicistronic construct expressing both enhanced green fluorescent protein and luciferase. We found that AAV2/8 and AAV2/7 mediate six- to eightfold higher levels of in vivo photoreceptor transduction than AAV2/5, considered so far the most efficient AAV serotype for photoreceptor targeting. In addition, following subretinal administration of AAV, the rhodopsin promoter allows significantly higher levels of photoreceptor expression than the other ubiquitous or photoreceptor-specific promoters tested. Finally, we show that AAV2/7, AAV2/8, and AAV2/9 outperform AAV2/5 following ex vivo transduction of retinal progenitor cells differentiated into photoreceptors. We conclude that AAV2/7 or AAV2/8 and the rhodopsin promoter provide the highest levels of photoreceptor transduction both in and ex vivo and that this may overcome the limitation to therapeutic success observed so far in models of inherited severe photoreceptor diseases.
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Ward, Rebecca, Joanna J. Kaylor, Diego F. Cobice, Dionissia A. Pepe, Eoghan M. McGarrigle, Susan E. Brockerhoff, James B. Hurley, Gabriel H. Travis, and Breandán N. Kennedy. "Non-photopic and photopic visual cycles differentially regulate immediate, early, and late phases of cone photoreceptor-mediated vision." Journal of Biological Chemistry 295, no. 19 (April 1, 2020): 6482–97. http://dx.doi.org/10.1074/jbc.ra119.011374.
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Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Müller glia. In the RPE, isomerization of all-trans-retinyl esters to 11-cis-retinol is mediated by the retinoid isomerohydrolase Rpe65. A putative alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Müller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early, and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, while the emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaptation displayed significantly attenuated immediate photopic vision concomitant with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 min of light, early photopic vision was recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde supplementation. Genetic knockout of Des1 (degs1) or retinaldehyde-binding protein 1b (rlbp1b) did not eliminate photopic vision in zebrafish. Our findings define molecular and temporal requirements of the nonphotopic or photopic visual cycles for mediating vision in bright light.
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SPRINGER, ALAN D. "New role for the primate fovea: A retinal excavation determines photoreceptor deployment and shape." Visual Neuroscience 16, no. 4 (July 1999): 629–36. http://dx.doi.org/10.1017/s0952523899164034.
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In humans, an increasing density of foveal cone photoreceptors occurs slowly over several years after birth, and accounts for a region that subserves high visual acuity. Concurrently, inner retinal cells move centrifugally away from the foveal center. Such developmental rearrangements reflect complex cellular remodeling after the retinal neuronal cells have differentiated and have formed synapses. Explaining foveal morphogenesis is difficult, because differentiated neuronal cells seem incapable of moving actively. Presented here is a biomechanical explanation of how the above events occur. This hypothesis assumes that the cellular movements throughout the retinal layers occur passively as the eye grows and the retina is stretched. Retinal stretch was simulated using virtual engineering models that were analyzed with finite element analysis. A pit combined with retinal stretch causes the retinal layers to deform in a way that accounts for both the centrifugal and centripetal movement of various retinal cell types. Axially directed, tensile forces associated with stretching the retinal tissue surrounding the pit also accounts for the elongated morphology of foveal cone photoreceptors. These simulations suggest that a pit is required for both the centripetal displacement of cone cells toward the center of the fovea, and for the elongated foveal cone morphology. Since the primate fovea may have minimal impact on acuity, its primary role may be to initiate foveal morphogenesis in slowly developing eyes.
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Sanyal, S., R. K. Hawkins, H. G. Jansen, and G. H. Zeilmaker. "Compensatory synaptic growth in the rod terminals as a sequel to partial photoreceptor cell loss in the retina of chimaeric mice." Development 114, no. 3 (March 1, 1992): 797–803. http://dx.doi.org/10.1242/dev.114.3.797.
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In the retina of chimaeric mice of rd and wild-type genotypic combination, selective loss of rd/rd photoreceptor cells, after initial development, leads to a mosaic retina with variable amounts of normal photoreceptor cells present over the retinal surface. In some of the rod terminals of these retinas the synaptic complexes with the second order retinal neurons are seen to contain multiple synaptic ribbons and an increased number of profiles of the postsynaptic elements. These changes are observed only in the rod terminals and not in the cone pedicles. Computer aided three-dimensional reconstruction of the altered synapses shows that these changes result from an increase in the number of synaptic sites, characterized by multiplication of the synaptic ribbons and enlargement of the second order neuronal processes. A quantitative analysis of such synapses, based on serial electron micrographs, shows that these are most frequently located in the retinal regions of the chimaeric individuals that have suffered maximum photoreceptor cell loss. Thus synaptic growth appears to take place as a reaction to the reduction of afferent input to the postsynaptic components. These findings demonstrate persistent synaptic plasticity in the rod terminals of mammalian retina during the maturational phase of late postnatal development. Compensatory synaptic growth in the rod terminals, as recorded here, can have important implications for the maintenance of visual sensitivity in the diseased or ageing retina.
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Kroeger, Heike, Julia M. D. Grandjean, Wei-Chieh Jerry Chiang, Daphne D. Bindels, Rebecca Mastey, Jennifer Okalova, Amanda Nguyen, et al. "ATF6 is essential for human cone photoreceptor development." Proceedings of the National Academy of Sciences 118, no. 39 (September 24, 2021): e2103196118. http://dx.doi.org/10.1073/pnas.2103196118.
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Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR regulator Activating Transcription Factor 6 (ATF6) cause severe congenital vision loss diseases such as achromatopsia by unclear pathomechanisms. To investigate this, we generated retinal organoids from achromatopsia patient induced pluripotent stem cells carrying ATF6 disease variants and from gene-edited ATF6 null hESCs. We found that achromatopsia patient and ATF6 null retinal organoids failed to form cone structures concomitant with loss of cone phototransduction gene expression, while rod photoreceptors developed normally. Adaptive optics retinal imaging of achromatopsia patients carrying ATF6 variants also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the defect in cone formation observed in our retinal organoids. These results establish that ATF6 is essential for human cone development. Interestingly, we find that a selective small molecule ATF6 signaling agonist restores the transcriptional activity of some ATF6 disease-causing variants and stimulates cone growth and gene expression in patient retinal organoids carrying these variants. These findings support that pharmacologic targeting of the ATF6 pathway can promote human cone development and should be further explored for blinding retinal diseases.
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Baba, Kenkichi, Varunika Goyal, and Gianluca Tosini. "Circadian Regulation of Retinal Pigment Epithelium Function." International Journal of Molecular Sciences 23, no. 5 (February 28, 2022): 2699. http://dx.doi.org/10.3390/ijms23052699.
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The retinal pigment epithelium (RPE) is a single layer of cells located between the choriocapillaris vessels and the light-sensitive photoreceptors in the outer retina. The RPE performs physiological processes necessary for the maintenance and support of photoreceptors and visual function. Among the many functions performed by the RPE, the timing of the peak in phagocytic activity by the RPE of the photoreceptor outer segments that occurs 1–2 h. after the onset of light has captured the interest of many investigators and has thus been intensively studied. Several studies have shown that this burst in phagocytic activity by the RPE is under circadian control and is present in nocturnal and diurnal species and rod and cone photoreceptors. Previous investigations have demonstrated that a functional circadian clock exists within multiple retinal cell types and RPE cells. However, the anatomical location of the circadian controlling this activity is not clear. Experimental evidence indicates that the circadian clock, melatonin, dopamine, and integrin signaling play a key role in controlling this rhythm. A series of very recent studies report that the circadian clock in the RPE controls the daily peak in phagocytic activity. However, the loss of the burst in phagocytic activity after light onset does not result in photoreceptor or RPE deterioration during aging. In the current review, we summarized the current knowledge on the mechanism controlling this phenomenon and the physiological role of this peak.
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Lopes, Vanda S., David Jimeno, Kornnika Khanobdee, Xiaodan Song, Bryan Chen, Steven Nusinowitz, and David S. Williams. "Dysfunction of Heterotrimeric Kinesin-2 in Rod Photoreceptor Cells and the Role of Opsin Mislocalization in Rapid Cell Death." Molecular Biology of the Cell 21, no. 23 (December 2010): 4076–88. http://dx.doi.org/10.1091/mbc.e10-08-0715.
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Due to extensive elaboration of the photoreceptor cilium to form the outer segment, axonemal transport (IFT) in photoreceptors is extraordinarily busy, and retinal degeneration is a component of many ciliopathies. Functional loss of heterotrimeric kinesin-2, a major anterograde IFT motor, causes mislocalized opsin, followed by rapid cell death. Here, we have analyzed the nature of protein mislocalization and the requirements for the death of kinesin-2-mutant rod photoreceptors. Quantitative immuno EM showed that opsin accumulates initially within the inner segment, and then in the plasma membrane. The light-activated movement of arrestin to the outer segment is also impaired, but this defect likely results secondarily from binding to mislocalized opsin. Unlike some other retinal degenerations, neither opsin–arrestin complexes nor photoactivation were necessary for cell loss. In contrast, reduced rod opsin expression provided enhanced rod and cone photoreceptor survival and function, as measured by photoreceptor cell counts, apoptosis assays, and ERG analysis. The cell death incurred by loss of kinesin-2 function was almost completely negated by Rho−/−. Our results indicate that mislocalization of opsin is a major cause of photoreceptor cell death from kinesin-2 dysfunction and demonstrate the importance of accumulating mislocalized protein per se, rather than specific signaling properties of opsin, stemming from photoactivation or arrestin binding.
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Polans, A. S., J. Buczyłko, J. Crabb, and K. Palczewski. "A photoreceptor calcium binding protein is recognized by autoantibodies obtained from patients with cancer-associated retinopathy." Journal of Cell Biology 112, no. 5 (March 1, 1991): 981–89. http://dx.doi.org/10.1083/jcb.112.5.981.
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Cancer-associated retinopathy (CAR), a paraneoplastic syndrome, is characterized by the degeneration of retinal photoreceptors under conditions where the tumor and its metastases have not invaded the eye. The retinopathy often is apparent before the diagnosis of cancer and may be associated with autoantibodies that react with specific sites in the retina. We have examined the sera from patients with CAR to further characterize the retinal antigen. Western blot analysis of human retinal proteins reveals a prominent band at 26 kD that is labeled by the CAR antisera. Antibodies to the 26-kD protein were affinity-purified from complex CAR antisera and used for EM-immunocytochemical localization of the protein to the nuclei, inner and outer segments of both rod and cone cells. Other antibodies obtained from the CAR sera did not label photoreceptors. Using the affinity-purified antibodies for detection, the 26-kD protein, designated p26, was purified to homogeneity from the outer segments of bovine rod photoreceptor cells by Phenyl-Sepharose and ion exchange chromatography. Partial amino acid sequence of p26 was determined by gas phase Edman degradation and revealed extensive homology with a cone-specific protein, visinin. Based upon structural relatedness, both the p26 rod protein and visinin are members of the calmodulin family and contain calcium binding domains of the E-F hand structure.
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Liu, Fei, Yayun Qin, Yuwen Huang, Pan Gao, Jingzhen Li, Shanshan Yu, Danna Jia, et al. "Rod genesis driven by mafba in an nrl knockout zebrafish model with altered photoreceptor composition and progressive retinal degeneration." PLOS Genetics 18, no. 3 (March 4, 2022): e1009841. http://dx.doi.org/10.1371/journal.pgen.1009841.
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Neural retina leucine zipper (NRL) is an essential gene for the fate determination and differentiation of the precursor cells into rod photoreceptors in mammals. Mutations in NRL are associated with the autosomal recessive enhanced S-cone syndrome and autosomal dominant retinitis pigmentosa. However, the exact role of Nrl in regulating the development and maintenance of photoreceptors in the zebrafish (Danio rerio), a popular animal model used for retinal degeneration and regeneration studies, has not been fully determined. In this study, we generated an nrl knockout zebrafish model via the CRISPR-Cas9 technology and observed a surprising phenotype characterized by a reduced number, but not the total loss, of rods and over-growth of green cones. We discovered two waves of rod genesis, nrl-dependent and -independent at the embryonic and post-embryonic stages, respectively, in zebrafish by monitoring the rod development. Through bulk and single-cell RNA sequencing, we characterized the gene expression profiles of the whole retina and each retinal cell type from the wild type and nrl knockout zebrafish. The over-growth of green cones and mis-expression of green-cone-specific genes in rods in nrl mutants suggested that there are rod/green-cone bipotent precursors, whose fate choice between rod versus green-cone is controlled by nrl. Besides, we identified the mafba gene as a novel regulator of the nrl-independent rod development, based on the cell-type-specific expression patterns and the retinal phenotype of nrl/mafba double-knockout zebrafish. Gene collinearity analysis revealed the evolutionary origin of mafba and suggested that the function of mafba in rod development is specific to modern fishes. Furthermore, the altered photoreceptor composition and abnormal gene expression in nrl mutants caused progressive retinal degeneration and subsequent regeneration. Accordingly, this study revealed a novel function of the mafba gene in rod development and established a working model for the developmental and regulatory mechanisms regarding the rod and green-cone photoreceptors in zebrafish.
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Nikonov, Sergei S., Lauren L. Daniele, Xuemei Zhu, Cheryl M. Craft, Anand Swaroop, and Edward N. Pugh. "Photoreceptors of Nrl −/− Mice Coexpress Functional S- and M-cone Opsins Having Distinct Inactivation Mechanisms." Journal of General Physiology 125, no. 3 (February 28, 2005): 287–304. http://dx.doi.org/10.1085/jgp.200409208.
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The retinas of mice null for the neural retina leucine zipper transcription factor (Nrl −/−) contain no rods but are populated instead with photoreceptors that on ultrastructural, histochemical, and molecular criteria appear cone like. To characterize these photoreceptors functionally, responses of single photoreceptors of Nrl −/− mice were recorded with suction pipettes at 35–37°C and compared with the responses of rods of WT mice. Recordings were made either in the conventional manner, with the outer segment (OS) drawn into the pipette (“OS in”), or in a novel configuration with a portion of the inner segment drawn in (“OS out”). Nrl −/− photoreceptor responses recorded in the OS-out configuration were much faster than those of WT rods: for dim-flash responses tpeak = 91 ms vs. 215 ms; for saturating flashes, dominant recovery time constants, τD = 110 ms vs. 240 ms, respectively. Nrl −/− photoreceptors in the OS-in configuration had reduced amplification, sensitivity, and slowed recovery kinetics, but the recording configuration had no effect on rod response properties, suggesting Nrl −/− outer segments to be more susceptible to damage. Functional coexpression of two cone pigments in a single mammalian photoreceptor was established for the first time; the responses of every Nrl −/− cell were driven by both the short-wave (S, λmax ≈ 360 nm) and the mid-wave (M, λmax ≈ 510 nm) mouse cone pigment; the apparent ratio of coexpressed M-pigment varied from 1:1 to 1:3,000 in a manner reflecting a dorso-ventral retinal position gradient. The role of the G-protein receptor kinase Grk1 in cone pigment inactivation was investigated in recordings from Nrl −/−/Grk1−/− photoreceptors. Dim-flash responses of cells driven by either the S- or the M-cone pigment were slowed 2.8-fold and 7.5-fold, respectively, in the absence of Grk1; the inactivation of the M-pigment response was much more seriously retarded. Thus, Grk1 is essential to normal inactivation of both S- and M-mouse cone opsins, but S-opsin has access to a relatively effective, Grk1-independent inactivation pathway.
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Kelley, M. W., J. K. Turner, and T. A. Reh. "Ligands of steroid/thyroid receptors induce cone photoreceptors in vertebrate retina." Development 121, no. 11 (November 1, 1995): 3777–85. http://dx.doi.org/10.1242/dev.121.11.3777.
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The mechanisms by which multipotent progenitor cells are directed to alternative cell identities during the histogenesis of the vertebrate central nervous system are likely to involve several different types of signaling systems. Recent evidence indicates that 9-cis retinoic acid, which acts through members of the steroid/thyroid superfamily of receptors, directs progenitor cells to the rod photoreceptor cell fate. We now report that another effector of this family of receptors, thyroid hormone, induces an increase in the number of cone photoreceptors that develop in embryonic rat retinal cultures, and that combinations of 9-cis retinoic acid and triiodothyronine cause isolated progenitor cells to differentiate as either rods or cones, depending on the relative concentrations of the ligands. These results implicate thyroid hormone in CNS cell fate determination, and suggest that different photoreceptor phenotypes may be modulated through the formation of thyroid/retinoid receptor heterodimers.
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Li, Zong-Yi, Jean H. Chang, and Ann H. Milam. "A gradient of basic fibroblast growth factor in rod photoreceptors in the normal human retina." Visual Neuroscience 14, no. 4 (July 1997): 671–79. http://dx.doi.org/10.1017/s0952523800012633.
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AbstractRetinitis pigmentosa (RP) is an inherited disease that causes primary degeneration of rod photoreceptors in the retina. Although the causal gene (e.g. rhodopsin) is thought to be expressed in all rods across the retina, the degeneration is typically nonuniform, with rods in the far periphery surviving significantly longer than those in the midperiphery and macula. Basic fibroblast growth factor (bFGF) is a putative survival factor for photoreceptors, and the characteristic regional pattern of rod cell survival in RP suggested that bFGF might be distributed nonuniformly in the human retina. We performed double-label immunocytochemistry on 15 normal human retinas, using anti-bFGF and other antibody markers for retinal neurons and glia. Immunoreactivity for bFGF was consistently absent from cones but was present in rods, populations of cone bipolar and amacrine cells, Müller glial cells, and astrocytes. In the macula, the percentage of bFGF-reactive rods was very low (~0.5%) but it increased in a central to peripheral gradient, accounting for up to ~88% of the rods in the far periphery. These findings suggest that a central to peripheral gradient of rod bFGF is present in normal human retina and may influence the pattern of photoreceptor degeneration in RP. The absence of bFGF in cones and the low number of bFGF-positive rods in the macula may correlate with the vulnerability of these cells in RP, age-related macular degeneration, and other retinal diseases.
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Leeper, H. F., and J. S. Charlton. "Response properties of horizontal cells and photoreceptor cells in the retina of the tree squirrel, Sciurus carolinensis." Journal of Neurophysiology 54, no. 5 (November 1, 1985): 1157–66. http://dx.doi.org/10.1152/jn.1985.54.5.1157.
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A new experimental preparation for intracellular recording from mammalian retinal neurons has been established. This is the arterially perfused eyecup preparation of the tree squirrel, Sciurus carolinensis. Two horizontal cell types have been recorded in this preparation. These cell types differ in their response waveforms. Type 1 horizontal cells appear to receive input only from cones, whereas type 2 horizontal cells receive mixed rod-cone input. Sciurus horizontal cells have receptive-field sizes smaller than those of horizontal cells in other mammalian and nonmammalian species. Recordings from a second class of cells in the outer retina of the squirrel reveal receptive-field properties considerably different from those of squirrel horizontal cells and similar to those of photoreceptor cells in other species. On the basis of these receptive-field properties, recording depth, and spectral response characteristics, we conclude that these recordings were from cone-photoreceptor cells. These recordings from squirrel cones are the first demonstration of mammalian photoreceptor response amplitudes and receptive-field interactions comparable with those demonstrated for nonmammalian species.
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Zhou, Yumei, Weiwei Xu, Anqi Liu, Ye Tao, Qun Wang, Yanfeng Yang, Liqiang Wang, and Yifei Huang. "Protective Effect of Salvianolic Acid A against N-Methyl-N-Nitrosourea-Induced Retinal Degeneration." Evidence-Based Complementary and Alternative Medicine 2022 (May 27, 2022): 1–10. http://dx.doi.org/10.1155/2022/1219789.
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Objective. Retinal degeneration (RD) is a serious, irreversible, and blinding eye disease, which seriously affects the visual function and quality of life of patients. At present, there is no effective method to treat RD. The final outcome of its development is photoreceptor cell oxidation and apoptosis. Therefore, looking for safe, convenient, and effective antioxidant therapy is still the key research field of Rd. In this study, the mice model of RD was induced by N-methyl-N-nitrosourea (MNU) in vivo to explore the therapeutic effect and mechanism of salvianolic acids (Sal A) on RD. In vitro, the protective effect of Sal A on MNU injured 661 W cell line of mouse retina photoreceptor cone cells was investigated preliminarily. Methods. Male C57BL/6 mice (7–8 weeks old) received a single intraperitoneal injection (ip) of 60 mg/kg MNU or vehicle control. Treatment groups then received Sal-A 0.5 mg/kg and 1.0 mg/kg via daily intravenous injections. On day 7, functional and morphological examinations were performed, including photopic and scotopic electroretinography (ERG) and hematological analyses to observe functional changes and damage to the outer nuclear layer (ONL). On the 3rd and 7th days, the levels of superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were determined. The expression of retinal Bax, Bcl-2, and caspase-3 was quantified by Western blot and RT-PCR assays. 661 W strain of mice retinal photoreceptor cone cells were cultured in vitro and treated with 1 µm MNU. The cells in the treatment group were given 50 μM Sal A as an intervention. The growth of 661 W cells was observed and recorded under an inverted light microscope, and the activity of cells was detected by the MTT method. Results. Sal A treatment was effective against MNU-induced RD in mice at both 0.5 mg/kg/d and 1.0 mg/kg/d doses, and the protective effect was dose-dependent. Sal A can alleviate MNU-mediated alterations to retinal ERG activity and can support maintenance of the thickness of the ONL layer. Sal A treatment increases the expression of retinal SOD and reduces the lipid peroxidation product MDA, suggesting that its protective effect is related to the oxidation resistance. It can offset changes to the expression of apoptotic factors in the retina caused by MNU treatment. Sal A mitigates MNU-mediated damage to cultured mice photoreceptor cone cells 661 W in vitro. Conclusion. Sal A alleviates the damage caused by MNU to retinal photoreceptor cells in vivo and in vivo, and its protective effect is related to its antioxidant and antiapoptotic activities.
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LITHERLAND, LENORE, and SHAUN P. COLLIN. "Comparative visual function in elasmobranchs: Spatial arrangement and ecological correlates of photoreceptor and ganglion cell distributions." Visual Neuroscience 25, no. 4 (July 2008): 549–61. http://dx.doi.org/10.1017/s0952523808080693.
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AbstractThe topographic analysis of retinal ganglion and photoreceptor cell distributions yields valuable information for assessing the visual capabilities and behavioral ecology of vertebrates. This study examines whole-mounted retinas of four elasmobranch species, the ornate wobbegong, Orectolobus ornatus; the whitetip reef shark, Triaenodon obesus; the epaulette shark, Hemiscyllium ocellatum; and the east Australia shovelnose ray, Aptychotrema rostrata, for regional specializations mediating zones of improved visual ability. These species represent a range of lifestyles: benthic, mid-water, diurnal, and nocturnal. Both photoreceptors (visualized using differential interference contrast optics) and ganglion cells (stained with cresyl violet) in the retina are extensively sampled, and their spatial distribution is found to be nonuniform, exhibiting areae or “visual streaks.” In general, the topographic distributions of both cell populations are in register and match well with respect to the location of regions of high density. However, the location of peaks in rod and cone densities can vary within a retina, indicating that preferential sampling of different regions of the visual field may occur in photopic and scotopic vision. Anatomical measures of the optical limits of resolving power, indicated by intercone spacing, range from 3.8 to 13.1 cycles/deg. Spatial limits of resolving power, calculated from ganglion cell spacing, range from 2.6 to 4.3 cycles/deg. Summation ratios, assessed by direct comparison of cell densities of photoreceptors (input cells) and ganglion cells (output cells), at more than 150 different loci across the retina, show topographic differences in signal convergence (ranging from 25:1 to over 70:1). Species-specific retinal specializations strongly correlate to the habitat and feeding behavior of each species.
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Tufford, Adele R., Jessica R. Onyak, Katelyn B. Sondereker, Jasmine A. Lucas, Aaron M. Earley, Pierre Mattar, Samer Hattar, Tiffany M. Schmidt, Jordan M. Renna, and Michel Cayouette. "Melanopsin Retinal Ganglion Cells Regulate Cone Photoreceptor Lamination in the Mouse Retina." Cell Reports 23, no. 8 (May 2018): 2416–28. http://dx.doi.org/10.1016/j.celrep.2018.04.086.
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Rossi, Ethan A., Charles E. Granger, Robin Sharma, Qiang Yang, Kenichi Saito, Christina Schwarz, Sarah Walters, et al. "Imaging individual neurons in the retinal ganglion cell layer of the living eye." Proceedings of the National Academy of Sciences 114, no. 3 (January 3, 2017): 586–91. http://dx.doi.org/10.1073/pnas.1613445114.
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Although imaging of the living retina with adaptive optics scanning light ophthalmoscopy (AOSLO) provides microscopic access to individual cells, such as photoreceptors, retinal pigment epithelial cells, and blood cells in the retinal vasculature, other important cell classes, such as retinal ganglion cells, have proven much more challenging to image. The near transparency of inner retinal cells is advantageous for vision, as light must pass through them to reach the photoreceptors, but it has prevented them from being directly imaged in vivo. Here we show that the individual somas of neurons within the retinal ganglion cell (RGC) layer can be imaged with a modification of confocal AOSLO, in both monkeys and humans. Human images of RGC layer neurons did not match the quality of monkey images for several reasons, including safety concerns that limited the light levels permissible for human imaging. We also show that the same technique applied to the photoreceptor layer can resolve ambiguity about cone survival in age-related macular degeneration. The capability to noninvasively image RGC layer neurons in the living eye may one day allow for a better understanding of diseases, such as glaucoma, and accelerate the development of therapeutic strategies that aim to protect these cells. This method may also prove useful for imaging other structures, such as neurons in the brain.
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Léveillard, Thierry, Nancy Philp, and Florian Sennlaub. "Is Retinal Metabolic Dysfunction at the Center of the Pathogenesis of Age-related Macular Degeneration?" International Journal of Molecular Sciences 20, no. 3 (February 11, 2019): 762. http://dx.doi.org/10.3390/ijms20030762.
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The retinal pigment epithelium (RPE) forms the outer blood–retina barrier and facilitates the transepithelial transport of glucose into the outer retina via GLUT1. Glucose is metabolized in photoreceptors via the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS) but also by aerobic glycolysis to generate glycerol for the synthesis of phospholipids for the renewal of their outer segments. Aerobic glycolysis in the photoreceptors also leads to a high rate of production of lactate which is transported out of the subretinal space to the choroidal circulation by the RPE. Lactate taken up by the RPE is converted to pyruvate and metabolized via OXPHOS. Excess lactate in the RPE is transported across the basolateral membrane to the choroid. The uptake of glucose by cone photoreceptor cells is enhanced by rod-derived cone viability factor (RdCVF) secreted by rods and by insulin signaling. Together, the three cells act as symbiotes: the RPE supplies the glucose from the choroidal circulation to the photoreceptors, the rods help the cones, and both produce lactate to feed the RPE. In age-related macular degeneration this delicate ménage à trois is disturbed by the chronic infiltration of inflammatory macrophages. These immune cells also rely on aerobic glycolysis and compete for glucose and produce lactate. We here review the glucose metabolism in the homeostasis of the outer retina and in macrophages and hypothesize what happens when the metabolism of photoreceptors and the RPE is disturbed by chronic inflammation.
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Vessey, John P., Melanie R. Lalonde, Hossein A. Mizan, Nicole C. Welch, Melanie E. M. Kelly, and Steven Barnes. "Carbenoxolone Inhibition of Voltage-Gated Ca Channels and Synaptic Transmission in the Retina." Journal of Neurophysiology 92, no. 2 (August 2004): 1252–56. http://dx.doi.org/10.1152/jn.00148.2004.
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We show that carbenoxolone, a drug used to block hemichannels in the retina to test the ephaptic model of horizontal cell inhibitory feedback, has strong inhibitory effects on voltage-gated Ca channels. Carbenoxolone (100 μM) reduced photoreceptor-to-horizontal cell synaptic transmission by 92%. Applied to patch-clamped, isolated cone photoreceptors, carbenoxolone inhibited Ca channels with an EC50 of 48 μM. At 100 μM, it reduced cone Ca channel current by 37%, reduced depolarization-evoked [Ca2+] signals in fluo-4 loaded retinal slices by 57% and inhibited Ca channels in Müller cells by 52%. A synaptic transfer model suggests that the degree of block of Ca channels accounts for the reduction in synaptic transmission. These results suggest broad inhibitory actions for carbenoxolone in the retina that must be considered when interpreting its effects on inhibitory feedback.
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Henderson, M. A., and T. G. Northcote. "Retinal Structure of Sympatric and Allopatric Populations of Cutthroat Trout (Salmo clarki clarki) and Dolly Varden Char (Salvelinus malma) in Relation to their Spatial Distribution." Canadian Journal of Fisheries and Aquatic Sciences 45, no. 7 (July 1, 1988): 1321–26. http://dx.doi.org/10.1139/f88-155.
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Retinal structures of cutthroat trout (Salmo clarki clarki) and Dolly Varden char (Salvelinus malma) were compared to determine if these features were consistent with the different light regimes in which the species live, depending on their sympatry or allopatry in lakes. Cone cell density in sympatric trout was over twice that of sympatric char and rod cell density was slightly less. The cross-sectional size of cone cells in sympatric trout was approximately 30% less than in sympatric char. The ratios of photoreceptor cells to ganglion cells in sympatric trout and char retinas were approximately 40:1 and 80:1, respectively. There were no differences between sympatric and allopatric trout with respect to these structural features. Estimates of cone cell density, cone size, and number of photoreceptor cells per ganglion cell for allopatric char were significantly different and intermediate between those for sympatric trout and char. All four populations had similar cone cell mosaics with four paired cones surrounding each single cone. Results are considered in relation to differences in vertical distribution and feeding of sympatric and allopatric populations in three study lakes.
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Xiang, Lue, Xue-Jiao Chen, Kun-Chao Wu, Chang-Jun Zhang, Gao-Hui Zhou, Ji-Neng Lv, Lan-Fang Sun, Fei-Fei Cheng, Xue-Bi Cai, and Zi-Bing Jin. "miR-183/96 plays a pivotal regulatory role in mouse photoreceptor maturation and maintenance." Proceedings of the National Academy of Sciences 114, no. 24 (May 30, 2017): 6376–81. http://dx.doi.org/10.1073/pnas.1618757114.
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MicroRNAs (miRNAs) are known to be essential for retinal maturation and functionality; however, the role of the most abundant miRNAs, the miR-183/96/182 cluster (miR-183 cluster), in photoreceptor cells remains unclear. Here we demonstrate that ablation of two components of the miR-183 cluster, miR-183 and miR-96, significantly affects photoreceptor maturation and maintenance in mice. Morphologically, early-onset dislocated cone nuclei, shortened outer segments and thinned outer nuclear layers are observed in the miR-183/96 double-knockout (DKO) mice. Abnormal photoreceptor responses, including abolished photopic electroretinography (ERG) responses and compromised scotopic ERG responses, reflect the functional changes in the degenerated retina. We further identify Slc6a6 as the cotarget of miR-183 and miR-96. The expression level of Slc6a6 is significantly higher in the DKO mice than in the wild-type mice. In contrast, Slc6a6 is down-regulated by adeno-associated virus-mediated overexpression of either miR-183 or miR-96 in wild-type mice. Remarkably, both silencing and overexpression of Slc6a6 in the retina are detrimental to the electrophysiological activity of the photoreceptors in response to dim light stimuli. We demonstrate that miR-183/96–mediated fine-tuning of Slc6a6 expression is indispensable for photoreceptor maturation and maintenance, thereby providing insight into the epigenetic regulation of photoreceptors in mice.
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Mohlin, Camilla, Dick Delbro, Anders Kvanta, and Kjell Johansson. "Evaluation of Congo Red Staining in Degenerating Porcine Photoreceptors In Vitro: Protective Effects by Structural and Trophic Support." Journal of Histochemistry & Cytochemistry 66, no. 9 (April 6, 2018): 631–41. http://dx.doi.org/10.1369/0022155418768222.
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Congo red (CR) is a histological stain used for the detection of extracellular amyloids mediating various neurodegenerative diseases. Given that damaged photoreceptors appear to degenerate similarly to other nerve cells, CR staining was evaluated in experimentally injured porcine retina. CR staining appeared mostly as discrete cytosolic deposits with no obvious plaque formation during the investigated time period. Increases of CR labeling coincided temporally with the known accumulation of mislocalized opsins and increases of cell death. Coculture, either with human retinal pigment epithelium (ARPE) or human neural progenitor (ReN) cells, was accompanied by a significant reduction of CR labeling. Of particular interest was the reduction of CR labeling in cone photoreceptors, which are important for the perception of color and fine details and afflicted in age-related macular degeneration (AMD). Electron microscopy revealed inclusions in the inner segment, cell body, and occasionally synaptic terminals of photoreceptor cells in cultured specimens. Closer examinations indicated the presence of different types of inclusions resembling protein aggregates as well as inclusion bodies. The current results indicate that injury-related response resulted in accumulation of CR deposits in photoreceptor cells, and that trophic and/or structural support attenuated this response.
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al-Ubaidi, M. R., R. L. Font, A. B. Quiambao, M. J. Keener, G. I. Liou, P. A. Overbeek, and W. Baehr. "Bilateral retinal and brain tumors in transgenic mice expressing simian virus 40 large T antigen under control of the human interphotoreceptor retinoid-binding protein promoter." Journal of Cell Biology 119, no. 6 (December 15, 1992): 1681–87. http://dx.doi.org/10.1083/jcb.119.6.1681.
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We have previously shown that postnatal expression of the viral oncoprotein SV40 T antigen in rod photoreceptors (transgene MOT1), at a time when retinal cells have withdrawn from the mitotic cycle, leads to photoreceptor cell death (Al-Ubaidi et al., 1992. Proc. Natl. Acad. Sci. USA. 89:1194-1198). To study the effect of the specificity of the promoter, we replaced the mouse opsin promoter in MOT1 by a 1.3-kb promoter fragment of the human IRBP gene which is expressed in both rod and cone photoreceptors during embryonic development. The resulting construct, termed HIT1, was injected into mouse embryos and five transgenic mice lines were established. Mice heterozygous for HIT1 exhibited early bilateral retinal and brain tumors with varying degrees of incidence. Histopathological examination of the brain and eyes of three of the families showed typical primitive neuroectodermal tumors. In some of the bilateral retinal tumors, peculiar rosettes were observed, which were different from the Flexner-Wintersteiner rosettes typically associated with human retinoblastomas. The ocular and cerebral tumors, however, contained Homer-Wright rosettes, and showed varying degrees of immunoreactivity to antibodies against the neuronal specific antigens, synaptophysin and Leu7, but not to antibodies against photoreceptor specific proteins. Taken together, the results indicate that the specificity of the promoter used for T antigen and/or the time of onset of transgene expression determines the fate of photoreceptor cells expressing T antigen.
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Fuhrmann, S., M. Kirsch, and H. D. Hofmann. "Ciliary neurotrophic factor promotes chick photoreceptor development in vitro." Development 121, no. 8 (August 1, 1995): 2695–706. http://dx.doi.org/10.1242/dev.121.8.2695.
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Previous in vitro studies have convincingly demonstrated the involvement of diffusible factors in the regulation of photoreceptor development. We now provide evidence that ciliary neurotrophic factor (CNTF) represents one of these regulatory molecules. In low density monolayer cultures prepared from embryonic day 8 chick retina, photoreceptor development was studied using the monoclonal antiopsin antibody rho-4D2 as a differentiation marker. The number of cells acquiring opsin immunoreactivity, determined after 3 days in vitro, was increased up to 4-fold in the presence of CNTF to maximally 10.5% of all cells. Basic fibroblast growth factor or taurine both of which have been reported to stimulate opsin expression in rat retinal cultures and other neurotrophic factors tested (nerve growth factor, brain derived neurotrophic factor) had no effect. The EC50 of the CNTF effect (2.6 pM) was virtually identical to that measured for other CNTF receptor mediated cellular responses. Conditioned medium produced by cultured retinal cells (most likely glial cells) exhibited opsin stimulating activity identical to that of CNTF. Stimulation of opsin expression was specific for morphologically less mature photoreceptors and obviously restricted to rods, since changes in the number of identifiable cone photoreceptors expressing opsin immunoreactivity (10% of all cones) were not detectable. Measurement of the kinetics of the CNTF response revealed that the factor acted on immature opsin-negative progenitors and that CNTF effects were unlikely to reflect enhanced cell survival. Proliferation of photoreceptors was also unaffected, as demonstrated by [3H]thymidine autoradiography. With prolonged culture periods a gradual decrease in the number of opsin-positive cells was observed both in controls and in the continuous presence of CNTF. This decrease could be partly prevented by the addition of 1 mM taurine. Our results suggest that CNTF acted as an inductive signal for uncommitted progenitor cells or during early stages of rod photoreceptor differentiation, whereas other extrinsic stimulatory activities seemed to be required for further maturation.