-
Pflugers Archiv : European Journal of... Sep 2021Rhodopsin is the light receptor in rod photoreceptor cells that initiates scotopic vision. Studies on the light receptor span well over a century, yet questions about... (Review)
Review
Rhodopsin is the light receptor in rod photoreceptor cells that initiates scotopic vision. Studies on the light receptor span well over a century, yet questions about the organization of rhodopsin within the photoreceptor cell membrane still persist and a consensus view on the topic is still elusive. Rhodopsin has been intensely studied for quite some time, and there is a wealth of information to draw from to formulate an organizational picture of the receptor in native membranes. Early experimental evidence in apparent support for a monomeric arrangement of rhodopsin in rod photoreceptor cell membranes is contrasted and reconciled with more recent visual evidence in support of a supramolecular organization of rhodopsin. What is known so far about the determinants of forming a supramolecular structure and possible functional roles for such an organization are also discussed. Many details are still missing on the structural and functional properties of the supramolecular organization of rhodopsin in rod photoreceptor cell membranes. The emerging picture presented here can serve as a springboard towards a more in-depth understanding of the topic.
Topics: Animals; Cell Membrane; Humans; Protein Multimerization; Protein Structure, Secondary; Retinal Rod Photoreceptor Cells; Rhodopsin
PubMed: 33591421
DOI: 10.1007/s00424-021-02522-5 -
Pflugers Archiv : European Journal of... Sep 2021All vertebrates share a canonical retina with light-sensitive photoreceptors in the outer retina. These photoreceptors are of two kinds: rods and cones, adapted to low... (Review)
Review
All vertebrates share a canonical retina with light-sensitive photoreceptors in the outer retina. These photoreceptors are of two kinds: rods and cones, adapted to low and bright light conditions, respectively. They both show a peculiar morphology, with long outer segments, comprised of ordered stacks of disc-shaped membranes. These discs host numerous proteins, many of which contribute to the visual transduction cascade. This pathway converts the light stimulus into a biological signal, ultimately modulating synaptic transmission. Recently, the zebrafish (Danio rerio) has gained popularity for studying the function of vertebrate photoreceptors. In this review, we introduce this model system and its contribution to our understanding of photoreception with a focus on the cone visual transduction cascade.
Topics: Animals; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Synapses; Vision, Ocular; Zebrafish
PubMed: 33598728
DOI: 10.1007/s00424-021-02528-z -
Investigative Ophthalmology & Visual... Apr 2020Analysis of photoreceptor morphology and gene expression in mispatterned eyes of zebrafish growth differentiation factor 6a (gdf6a) mutants.
PURPOSE
Analysis of photoreceptor morphology and gene expression in mispatterned eyes of zebrafish growth differentiation factor 6a (gdf6a) mutants.
METHODS
Rod and cone photoreceptors were compared between gdf6a mutant and control zebrafish from larval to late adult stages using transgenic labels, immunofluorescence, and confocal microscopy, as well as by transmission electron microscopy. To compare transcriptomes between larval gdf6a mutant and control zebrafish, RNA-Seq was performed on isolated eyes.
RESULTS
Although rod and cone photoreceptors differentiate in gdf6a mutant zebrafish, the cells display aberrant growth and morphology. The cone outer segments, the light-detecting sensory endings, are reduced in size in the mutant larvae and fail to recover to control size at subsequent stages. In contrast, rods form temporarily expanded outer segments. The inner segments, which generate the required energy and proteins for the outer segments, are shortened in both rods and cones at all stages. RNA-Seq analysis provides a set of misregulated genes associated with the observed abnormal photoreceptor morphogenesis.
CONCLUSIONS
GDF6 mutations were previously identified in patients with Leber congenital amaurosis. Here, we reveal a unique photoreceptor phenotype in the gdf6a mutant zebrafish whereby rods and cones undergo abnormal maturation distinct for each cell type. Further, subsequent development shows partial recovery of cell morphology and maintenance of the photoreceptor layer. By conducting a transcriptomic analysis of the gdf6a larval eyes, we identified a collection of genes that are candidate regulators of photoreceptor size and morphology.
Topics: Animals; Fluorescent Antibody Technique; Gene Expression Regulation, Developmental; Growth Differentiation Factor 6; In Situ Hybridization; Larva; Microscopy, Confocal; Microscopy, Electron, Transmission; Morphogenesis; Mutation; Paraffin Embedding; Real-Time Polymerase Chain Reaction; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Zebrafish; Zebrafish Proteins
PubMed: 32293666
DOI: 10.1167/iovs.61.4.9 -
Cell Reports Nov 2021Gene regulatory networks (GRNs), consisting of transcription factors and their target sites, control neurogenesis and cell-fate specification in the developing central...
Gene regulatory networks (GRNs), consisting of transcription factors and their target sites, control neurogenesis and cell-fate specification in the developing central nervous system. In this study, we use integrated single-cell RNA and single-cell ATAC sequencing (scATAC-seq) analysis in developing mouse and human retina to identify multiple interconnected, evolutionarily conserved GRNs composed of cell-type-specific transcription factors that both activate genes within their own network and inhibit genes in other networks. These GRNs control temporal patterning in primary progenitors, regulate transition from primary to neurogenic progenitors, and drive specification of each major retinal cell type. We confirm that NFI transcription factors selectively activate expression of genes promoting late-stage temporal identity in primary retinal progenitors and identify other transcription factors that regulate rod photoreceptor specification in postnatal retina. This study inventories cis- and trans-acting factors that control retinal development and can guide cell-based therapies aimed at replacing retinal neurons lost to disease.
Topics: Animals; Body Patterning; Cell Differentiation; Cell Lineage; Eye Proteins; Female; Gene Expression; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Homeodomain Proteins; Humans; Male; Mice; NFI Transcription Factors; Neurogenesis; Retina; Retinal Neurons; Retinal Rod Photoreceptor Cells; Trans-Activators
PubMed: 34788628
DOI: 10.1016/j.celrep.2021.109994 -
Investigative Ophthalmology & Visual... Apr 2023To characterize the association between dark-adapted rod and cone sensitivity and retinal structure in PAX6-related aniridia.
PURPOSE
To characterize the association between dark-adapted rod and cone sensitivity and retinal structure in PAX6-related aniridia.
METHODS
Dark-adaptation curves were measured after a 5-minute exposure to bright light with red (625 nm) and green (527 nm) 2° circular light stimuli presented at ≈20° temporal retinal eccentricity in 27 participants with aniridia (nine males; 11-66 years old) and 38 age-matched healthy controls. A two-stage exponential model was fitted to each participant's responses to determine their cone and rod thresholds over time. The thicknesses of macular inner and outer retinal layers were obtained from optical coherence tomography images in 20 patients with aniridia and the 38 healthy controls. Aniridia-associated keratopathy (AAK) grade (0-3) and lens opacities were quantified by clinical examination of the anterior segment.
RESULTS
The rod-cone break time was similar between patients with aniridia and healthy controls. Dark-adapted cone and the rod thresholds were higher in aniridia compared with healthy controls. In aniridia, foveal outer retinal layer thickness correlated with both final cone and rod thresholds. A multiple regression model indicated that foveal outer retinal layer thickness and age were the main explanatory variables to predict both final cone and rod thresholds in aniridia when the AAK grade was 2 or less.
CONCLUSIONS
The results show that both rod- and cone-related functions are affected in PAX6-related aniridia and suggest that retinal anatomical and physiological changes extend beyond the area commonly studied in this condition: the central macula.
Topics: Male; Humans; Child; Adolescent; Young Adult; Adult; Middle Aged; Aged; Dark Adaptation; Retina; Retinal Cone Photoreceptor Cells; Photoreceptor Cells, Vertebrate; Vision Disorders; Corneal Diseases; Aniridia; Tomography, Optical Coherence
PubMed: 37067366
DOI: 10.1167/iovs.64.4.18 -
The Journal of Physiology Jul 2021Most vertebrate eyes have rod and cone photoreceptors, which use a signal transduction pathway consisting of many biological processes to transform light into an...
KEY POINTS
Most vertebrate eyes have rod and cone photoreceptors, which use a signal transduction pathway consisting of many biological processes to transform light into an electrical response. We dissect and quantify the contribution of each of these processes to the photoreceptor light response by using a novel method of analysis that provides an analytical solution for the entire time course of the dim-flash light response. We find that the shape of the light response is exclusively controlled by deactivation parameters. Activation parameters scale this shape and alter the response amplitude. We show that the rising phase of the response depends on Ca feedback, and we identify the deactivation parameters that control the recovery phase of the response. We devise new methods to extract values for deactivation and activation parameters from a separate analysis of response shape and response amplitude.
ABSTRACT
Vertebrate eyes have rod and cone photoreceptors, which use a complex transduction pathway comprising many biological processes to transform the absorption of light into an electrical response. A fundamental question in sensory transduction is how these processes contribute to the response. To study this question, we use a well-accepted phototransduction model, which we analyse with a novel method based on the log transform of the current. We derive an analytical solution that describes the entire time course of the photoreceptor response to dim flashes of light. We use this solution to dissect and quantify the contribution of each process to the response. We find that the entire dim-flash response is proportional to the flash intensity. By normalizing responses to unit amplitude, we define a waveform that is independent of the light intensity and characterizes the invariant shape of dim-flash responses. We show that this waveform is exclusively determined by deactivation rates; activation rates only scale the waveform and affect the amplitude. This analysis corrects a previous assumption that the rising phase is determined entirely by activation rates. We further show that the rising phase depends on Ca feedback to the cyclase, contrary to current belief. We identify the deactivation rates that control the recovery phase of the response, and we devise new methods to extract activation and deactivation rates from an analysis of response shape and response amplitude. In summary, we provide a comprehensive understanding of how the various transduction processes produce the cellular response.
Topics: Animals; Feedback; Mice; Photic Stimulation; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Signal Transduction
PubMed: 33977528
DOI: 10.1113/JP281225 -
International Ophthalmology May 2022To assess the effect of central and peripheral stimulation on the pupillary light reflex. The aim was to detect possible differences between cone- and rod-driven...
PURPOSE
To assess the effect of central and peripheral stimulation on the pupillary light reflex. The aim was to detect possible differences between cone- and rod-driven reactions.
METHODS
Relative maximal pupil constriction amplitude (relMCA) and latency to constriction onset (latency) to cone- and rod-specific stimuli of 30 healthy participants (24 ± 5 years (standard deviation)) were measured using chromatic pupil campimetry. Cone- and rod-specific stimuli had different intensities and wavelengths according to the Standards in Pupillography. Five filled circles with radii of 3°, 5°, 10°, 20° and 40° and four rings with a constant outer radius of 40° and inner radii of 3°, 5°, 10° and 20° were used as stimuli.
RESULTS
For cone-and rod-specific stimuli, relMCA increased with the stimulus area for both, circles and rings. However, increasing the area of a cone-specific ring by minimizing its inner radius with constant outer radius increased relMCA significantly stronger than the same did for a rod-specific ring. For cones and rods, a circle stimulus with a radius of 40° created a lower relMCA than the summation of the relMCAs to the corresponding ring and circle stimuli which combined create a 40° circle-stimulus. Latency was longer for rods than for cones. It decreased with increasing stimulus area for circle stimuli while it stayed nearly constant with increasing ring stimulus area for cone- and rod-specific stimuli.
CONCLUSION
The effect of central stimulation on relMCA is more dominant for cone-specific stimuli than for rod-specific stimuli while latency dynamics are similar for both conditions.
Topics: Humans; Light; Miosis; Photic Stimulation; Pupil; Reflex, Pupillary; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells
PubMed: 34826023
DOI: 10.1007/s10792-021-02132-1 -
The Journal of Comparative Neurology Aug 2023The light pathways are segregated into rod and cone pathways in which rods synapse with rod bipolar cells (RBCs), while cones contact cone bipolar cells (CBCs). However,...
The light pathways are segregated into rod and cone pathways in which rods synapse with rod bipolar cells (RBCs), while cones contact cone bipolar cells (CBCs). However, previous studies found that cones can make synapse with RBCs (cone-RBC synapses) and rods can contact OFF CBC in primate and rabbit retinas. Recently, such cone-RBC synapses have been reported physiologically and morphologically in the mouse retina. Nevertheless, the precise subcellular evidence to determine whether it is the invaginating synapse or the flat contact remains absent. This is due to a lack of immunochemically verified ultrastructural data. Here, we investigated the precise expression of protein kinase C alpha (PKCα) using pre-embedding immunoelectron microscopy (immuno-EM) with a monoclonal antibody against PKCα, a biomarker for the RBCs. We determined the nanoscale localization of PKCα in the outer plexiform layer of the mouse and guinea pig retinas. Our results demonstrate the existence of both the direct invaginating synapse and the basal/flat contact of the cone-RBCs, providing for the first time immunochemically verified ultrastructural evidence for the cone-RBC synapse in the mouse and guinea pig retinas. These results suggest that the cross talk between cone and rod pathways is much more extensive than previously assumed.
Topics: Guinea Pigs; Mice; Animals; Rabbits; Retinal Cone Photoreceptor Cells; Protein Kinase C-alpha; Retina; Retinal Bipolar Cells; Synapses; Photoreceptor Cells
PubMed: 37073449
DOI: 10.1002/cne.25487 -
The Journal of Physiology Sep 2020Most vertebrate eyes have rods for dim-light vision and cones for brighter light and higher temporal sensitivity. Rods evolved from cone-like precursors through...
KEY POINTS
Most vertebrate eyes have rods for dim-light vision and cones for brighter light and higher temporal sensitivity. Rods evolved from cone-like precursors through expression of different transduction genes or the same genes at different expression levels, but we do not know which molecular differences were most important. We approached this problem by analysing rod and cone responses with the same model but with different values for model parameters. We showed that, in addition to outer-segment volume, the most important differences between rods and cones are: (1) decreased transduction gain, reflecting smaller amplification in the G-protein cascade; (2) a faster rate of turnover of the second messenger cGMP in darkness; and (3) an accelerated rate of decay of the effector enzyme phosphodiesterase and perhaps also of activated visual pigment. We believe our analysis has identified the principal alterations during evolution responsible for the duplex retina.
ABSTRACT
Most vertebrates have rod and cone photoreceptors, which differ in their sensitivity and response kinetics. We know that rods evolved from cone-like precursors through the expression of different transduction genes or the same genes at different levels, but we do not know which molecular differences were most important. We have approached this problem in mouse retina by analysing the kinetic differences between rod flash responses and recent voltage-clamp recordings of cone flash responses, using a model incorporating the principal features of photoreceptor transduction. We apply a novel method of analysis using the log-transform of the current, and we ask which of the model's dynamic parameters need be changed to transform the flash response of a rod into that of a cone. The most important changes are a decrease in the gain of the response, reflecting a reduction in amplification of the transduction cascade; an increase in the rate of turnover of cGMP in darkness; and an increase in the rate of decay of activated phosphodiesterase, with perhaps also an increase in the rate of decay of light-activated visual pigment. Although we cannot exclude other differences, and in particular alterations in the Ca economy of the photoreceptors, we believe that we have identified the kinetic parameters principally responsible for the differences in the flash responses of the two kinds of photoreceptors, which were likely during evolution to have resulted in the duplex retina.
Topics: Animals; Kinetics; Mice; Retina; Retinal Cone Photoreceptor Cells; Retinal Pigments; Retinal Rod Photoreceptor Cells
PubMed: 32557629
DOI: 10.1113/JP279524 -
Scientific Reports Feb 2022Delayed dark adaptation due to impaired rod photoreceptor homeostasis has been reported as the earliest symptom of eye diseases such as age-related macular degeneration,...
Delayed dark adaptation due to impaired rod photoreceptor homeostasis has been reported as the earliest symptom of eye diseases such as age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa. Objective measurement of dark adaptation can facilitate early diagnosis to enable prompt intervention to prevent vision loss. However, there is a lack of noninvasive methods capable of spatiotemporal monitoring of photoreceptor changes during dark adaptation. Here we demonstrate functional optical coherence tomography (OCT) for in vivo intrinsic signal optoretinography (ORG) of dark adaptation kinetics in the C57BL/6J mouse retina. Functional OCT revealed a shortening of the outer retina, a rearrangement of the cone and rod photoreceptor interdigitation zone, and a reduction in intrinsic signal amplitude at the photoreceptor inner segment ellipsoid (ISe). A strong positive correlation between the outer retinal shortening and ISe intensity reduction was also confirmed. Functional OCT of dark adaptation kinetics promises an objective method for rapid ORG assessment of physiological integrity of retinal photoreceptors.
Topics: Animals; Blindness; Dark Adaptation; Diabetic Retinopathy; Early Diagnosis; Kinetics; Macular Degeneration; Mice, Inbred C57BL; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa; Tomography, Optical Coherence; Mice
PubMed: 35169239
DOI: 10.1038/s41598-022-06562-4