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PubMed2005

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

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

Animals↗

PubMedDate not supplied

Patch-clamp recording of human retinal photoreceptors and bipolar cells.

Photoreceptors and retinal bipolar cells are considered as nonspiking neurons; however, we recently showed that human rod photoreceptors can generate sodium action potentials in response to membrane depolarization from membrane potentials of -60 or -70 mV (Kawai et al., Neuron 30 [2001] 451). We performed patch-clamp recording of human cone photoreceptors and retinal bipolar cells to examine whether functional voltage-gated sodium channels are expressed in these cells as well as rod photoreceptors. Under current-clamp conditions, the injection of depolarizing current steps into a cone photoreceptor-induced marked action potentials. These action potentials were blocked by 1 microM tetrodotoxin, a voltage-gated sodium channel blocker. Under voltage-clamp conditions, depolarizing voltage steps-induced a fast transient inward current in several bipolar cells (n = 4/78). This current was activated from -70 to + 20 mV (maximal at -10 mV) and inactivated within 5 ms. The 10-90% rise time of this current was shorter than another inward current (less than one-hundredth). These results indicate that human cones and bipolar cells express voltage-gated sodium channels as rod photoreceptors. Sodium channels may serve to amplify the release of a neurotransmitter and to accelerate the light-dark change in photosignals.

Adult↗

PubMed1957

The structure and concentration of solids in photoreceptor cells studied by refractometry and interference microscopy.

Fragments of freshly obtained retinas of several vertebrate species were studied by refractometry, with reference to the structure of the rods and cones. The findings allowed a reassessment of previous descriptions based mainly on fixed material. The refractometric method was used also to measure the refractice indices and to calculate the concentrations of solids and water in the various cell segments. The main quantitative data were confirmed by interference microscopy. When examined by the method of refractometry the outer segments of freshly prepared retinal rods appear homogeneous. Within a few minutes a single eccentric longitudinal fiber appears, and transverse striations may develop. These changes are attributed to imbibition of water and swelling in structures normally too small for detection by light microscopy. The central "core" of outer segments and the chromophobic disc between outer and inner segments appear to be artifacts resulting from shrinkage during dehydration. The fresh outer segments of cones, and the inner segments of rods and cones also are described and illustrated. The volumes, refractive indices, concentrations of solids, and wet and dry weights of various segments of the photoreceptor cells were tabulated. Rod outer segments of the different species vary more than 100-fold in volume and mass but all have concentrations of solids of 40 to 43 per cent. Cone outer segments contain only about 30 per cent solids. The myoids, paraboloids, and ellipsoids of the inner segments likewise have characteristic refractive indices and concentrations of solids. Some of the limitations and particular virtues of refractometry as a method for quantitative analysis of living cells are discussed in comparison with more conventional biochemical techniques. Also the shapes and refractive indices of the various segments of photoreceptor cells are considered in relation to the absorption and transmission of light. The Stiles-Crawford effect can be accounted for on the basis of the structure of cone cells.

Histological Techniques↗

PubMed2005

Retinal regional differences in photoreceptor cell death and regeneration in light-lesioned albino zebrafish.

Teleost fish regenerate retinal cells from a population of inner nuclear layer (INL) stem cells. To characterize photoreceptor regeneration in zebrafish (Danio rerio), adult albino fish were subjected to constant intense light to cause photoreceptor cell death. Retinal morphometry was performed on histological sections of control and light-lesioned albino retinas to compare the extent of light damage in the ventral, central and dorsal retinal regions. In addition, opsin immunohistochemistry and TUNEL were used to compare photoreceptor cell death in these different retinal areas, while PCNA immunolabeling quantified the cell proliferation that precedes the photoreceptor regeneration. Transgenic albino; Tg(alpha1-tubulin:egfp) zebrafish were also exposed to the intense light in order to examine regeneration-related gene expression changes. The light-lesioned retinas are characterized by extensive rod and cone photoreceptor cell death in the central and dorsal regions. In contrast, many of the rods and cones survive in the ventral retina. The highest levels of INL cell proliferation, which occurs subsequent to photoreceptor death, correspond to the retinal regions that suffer the greatest levels of photoreceptor damage. In the ventral retina, where photoreceptor cell death is minimal, cell proliferation is confined to the ONL. In addition, EGFP expression from the alpha1-tubulin promoter is increased in Müller glial cells in the light-damaged central and dorsal retina, while transgene expression in the ventral retina is restricted to small, round INL cells. Furthermore, expression of the HuC/D neuronal antigen is detected in a subpopulation of the Müller cells in the light-damaged superior retinal region. These data demonstrate that adult albino zebrafish display retinal regional differences in photoreceptor cell death and in the regeneration-related INL cell proliferation response. The high levels of INL cell proliferation and alpha1-tubulin:egfp transgene expression in the Müller cells may be graded in response to the degree of photoreceptor cell death. This suggests that the levels of photoreceptor damage may directly influence cell responses in the underlying retinal layers.

Animals↗

PubMed2003

BETA2/NeuroD1 null mice: a new model for transcription factor-dependent photoreceptor degeneration.

BETA2/NeuroD1 is a basic helix-loop-helix transcription factor that is expressed widely throughout the developing nervous system. Previous studies have shown that BETA2/NeuroD1 influences the fate of retinal cells in culture. To analyze the effect of BETA2/NeuroD1 on the structure and function of the retina, we examined a line of BETA2/NeuroD1 knock-out mice that survives until adulthood. At 2-3 months of age, homozygous null mice showed a 50% reduction in rod-driven electroretinograms (ERGs) and a 65% reduction in cone-driven ERGs. ERGs measured from knock-out mice that were >9 months of age were undetectable. At 2-3 months, the number of photoreceptors in the outer nuclear layer was reduced by 50%. In addition, electron microscopy showed that the surviving photoreceptors had shortened outer segments. The number of cones labeled by peanut agglutinin was decreased 50-60%. By 18 months, retinas from null mice were completely devoid of photoreceptors. There appeared to be few changes in the inner retina, although BETA2/NeuroD1 is expressed in this area. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling staining revealed a dramatic increase in cell death, peaking at approximately postnatal day 3 and continuing into adulthood. No defects in cell birth were detected using bromodeoxyuridine staining. Our results reveal that BETA2/NeuroD1 not only plays an important role in terminal differentiation of photoreceptors but also serves as a potential survival factor. Loss of BETA2/NeuroD1 results in an age-related degeneration of both rods and cones.

Animals↗

PubMed1995

Light responses from one type of ON-OFF amacrine cells in the rabbit retina.

1. The light responses from one type of ON-OFF amacrine cell were recorded intracellularly in the superfused rabbit retina under various conditions of light adaptation. These recordings were obtained from cells located in a central area. 5-7 mm inferior and directly below the optic nerve head. 2. ON-OFF amacrine cells responded to the initiation and termination of light stimuli with transient depolarizations. Their receptive fields were approximately 0.8-1 mm diam and did not exhibit antagonistic center-and-surround organization. 3. The cells received rod input because they responded to very dim scotopic stimuli. With prolonged dark adaptation, the cells became more sensitive to the initiation than termination of the stimulus, because the ON component of the light response had a lower threshold than the OFF component. 4. The cells continued to respond to test flashes when the retina was adapted to a background illumination of rod-saturating intensity. Thus ON-OFF amacrine cells also receive cone input. Under these photopic conditions, a secondary afterpotential was observed following the OFF component. Its characteristics were different from those of the rod aftereffect reported in other retinal cells of the rabbit because its latency and amplitude changed with increasing stimulus intensity. 5. Intracellular injections of horseradish peroxidase showed that the recordings were obtained from a class of ON-OFF amacrine cells whose wide-field, unistratified dendrites were rigorously confined to the middle of the inner plexiform layer or stratum 3. 6. The conspicuous rod and cone inputs into a class of amacrine cells that are connected neither to rod bipolars nor to All amacrine cells strongly support the idea that in the rabbit the rod pathway uses cone bipolars as interneurons to distribute scotopic signals to ganglion and cone-driven amacrine cells.

Animals↗

PubMed2000

Photoreceptor distribution in the retinas of subprimate mammals.

Relevant data on the distribution of color cones are summarized, with special emphasis on the marked dorsoventral asymmetries observed in a number of mammalian species. In addition, an overview is given of studies that demonstrate the coexistence of two visual pigments within the same cone cell. The biological significance of these phenomena is discussed in conjunction with comparative immunocytochemical analyses of subprimate retinas. Based on various cone distribution patterns and temporal and spatial visual pigment coexpression, two models of cone photoreceptor differentiation are suggested.

Animals↗

PubMed2006

Visual cycle: Dependence of retinol production and removal on photoproduct decay and cell morphology.

The visual cycle is a chain of biochemical reactions that regenerate visual pigment following exposure to light. Initial steps, the liberation of all-trans retinal and its reduction to all-trans retinol by retinol dehydrogenase (RDH), take place in photoreceptors. We performed comparative microspectrophotometric and microfluorometric measurements on a variety of rod and cone photoreceptors isolated from salamander retinae to correlate the rates of photoproduct decay and retinol production. Metapigment decay rate was spatially uniform within outer segments and 50-70 times faster in the cells that contained cone-type pigment (SWS2 and M/LWS) compared to cells with rod-type pigment (RH1). Retinol production rate was strongly position dependent, fastest at the base of outer segments. Retinol production rate was 10-40 times faster in cones with cone pigments (SWS2 and M/LWS) than in the basal OS of rods containing rod pigment (RH1). Production rate was approximately five times faster in rods containing cone pigment (SWS2) than the rate in basal OS of rods containing the rod pigment (RH1). We show that retinol production is defined either by metapigment decay rate or RDH reaction rate, depending on cell type or outer segment region, whereas retinol removal is defined by the surface-to-volume ratio of the outer segment and the availability of retinoid binding protein (IRBP). The more rapid rates of retinol production in cones compared to rods are consistent with the more rapid operation of the visual cycle in these cells.

Ambystoma↗

PubMedDate not supplied

Movement of retinal along cone and rod photoreceptors.

Single 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.

Ambystoma↗

PubMed2000

Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate.

Hereditary human retinal degenerative diseases usually affect the mature photoreceptor topography by reducing the number of cells through apoptosis, resulting in loss of visual function. Only one inherited retinal disease, the enhanced S-cone syndrome (ESCS), manifests a gain in function of photoreceptors. ESCS is an autosomal recessive retinopathy in which patients have an increased sensitivity to blue light; perception of blue light is mediated by what is normally the least populous cone photoreceptor subtype, the S (short wavelength, blue) cones. People with ESCS also suffer visual loss, with night blindness occurring from early in life, varying degrees of L (long, red)- and M (middle, green)-cone vision, and retinal degeneration. The altered ratio of S- to L/M-cone photoreceptor sensitivity in ESCS may be due to abnormal cone cell fate determination during retinal development. In 94% of a cohort of ESCS probands we found mutations in NR2E3 (also known as PNR), which encodes a retinal nuclear receptor recently discovered to be a ligand-dependent transcription factor. Expression of NR2E3 was limited to the outer nuclear layer of the human retina. Our results suggest that NR2E3 has a role in determining photoreceptor phenotype during human retinogenesis.

Amino Acid Sequence↗

PubMed1996

Retinoic acid alters photoreceptor development in vivo.

Application of exogenous retinoic acid (RA) to zebrafish during the initial stages of photoreceptor differentiation results in a precocious development of rod photoreceptors and an inhibition of cone photoreceptor maturation. The acceleration of rod differentiation is observed initially within the ventral retina 3 days after fertilization, following 24 hr of RA application, and within the dorsal retina 4 days after fertilization, following 48 hr of RA application. The differentiation of rods was impeded significantly when the synthesis of endogenous retinoic acid was inhibited by citral prior to the initial stage of rod differentiation. RA-treated embryos labeled for bromodeoxyuridine (BrdU) uptake revealed that RA exerts its effect on a postmitotic cell population within the developing retina. During normal development in zebrafish, rod differentiation is most robust within the ventral retina, a region previously shown to be rich in RA. Our data suggest that the RA signaling pathway is involved in the differentiation and maturation of both the rod and cone photoreceptors within the developing zebrafish retina.

Animals↗

PubMed1997

Migration and synaptogenesis of cone photoreceptors in the developing mouse retina.

Mouse retinal photoreceptor cell generation and morphogenesis take place in a well-characterized temporal sequence. Both rod and cone photoreceptor differentiation and synaptogenesis occur postnatally, but the relative timing of these events has been difficult to document due to the paucity of cell-specific markers. We have found that antibodies to neuron-specific enolase (NSE) preferentially label a subpopulation of photoreceptors in the outer nuclear layer (ONL) of the mouse retina in addition to labeling ganglion, amacrine, bipolar, and horizontal cells within the inner layers of the retina. The appearance of NSE immunoreactivity in the different classes of retinal neurons during development showed a close temporal relationship to the onset of expression of the synaptic vesicle-associated protein SV2 and clearly preceded the sequential development of synaptic connections in both inner and outer synaptic layers. The NSE-immunoreactive photoreceptors were identified as cones by dual labeling of their inner segments with the lectin peanut agglutinin or by colabeling with antisera to cone photopigments. Axonal extensions of NSE-labeled cone cells were shown to interact with those of differentiating horizontal cells as early as postnatal day 3 (P3). Colocalization of NSE with SV2 indicated that cone cells began to make synaptic contacts with horizontal cell processes several days prior to the development of rod synaptic terminals. Between P4 and P11, cone photoreceptor cell nuclei were observed to be scattered at various levels throughout the ONL and thus appeared to have become displaced from their previous position directly beneath the outer limiting membrane (OLM). By P12, the cone nuclei had migrated sclerad once again and were now observed to be neatly aligned adjacent to the OLM. In the rd mouse mutant, this migratory process was delayed, so that, at P12, positioning of the cone cell nuclei within the ONL was still quite irregular. Thus, we have identified a late migratory phase for cone photoreceptors during the second week after birth that correlates with the timing of maturation of the rod synaptic terminals just prior to eye opening. The types of cues used by maturing cone cells for their eventual sclerad location remain to be elucidated.

Animals↗

PubMed2000

Müller cell outgrowth after retinal detachment: association with cone photoreceptors.

PURPOSE: Subretinal gliosis is a relatively common occurrence after retinal reattachment. Because Müller cell processes only intermittently penetrate the outer limiting membrane (OLM) beneath extensive detachments, this study was conducted to determine whether this was preferentially associated with rod or cone photoreceptors. METHODS: Cat retinas were detached from the retinal pigment epithelium and 3 days later were fixed in 4% paraformaldehyde, embedded in 5% agarose, sectioned at 100 microm, and processed for standard immuohistochemistry. The retinas were double labeled with either anti-vimentin and anti-long/medium wavelength-sensitive (anti-L/M) cone opsin or anti-glial fibrillary acidic protein (GFAP) and biotinylated peanut agglutinin (PNA). RESULT: The hypertrophy of Muller cells was readily traced using antibodies to vimentin and GFAP. When labeling with these antibodies was combined with labeling by either antibodies to cone opsins or biotinylated PNA, a consistent relationship was observed between the Müller cell processes growing through the OLM and cone photoreceptors. CONCLUSIONS. The growth of Müller cell processes into the subretinal space forms a fibrotic layer that completely inhibits the regeneration of outer segments. The current results show that there appears to be a highly specific interaction between growing Müller cell processes and cone photoreceptors during the earliest phase in this process.

Animals↗

PubMed2002

Connexin36 is essential for transmission of rod-mediated visual signals in the mammalian retina.

To examine the functions of electrical synapses in the transmission of signals from rod photoreceptors to ganglion cells, we generated connexin36 knockout mice. Reporter expression indicated that connexin36 was present in multiple retinal neurons including rod photoreceptors, cone bipolar cells, and AII amacrine cells. Disruption of electrical synapses between adjacent AIIs and between AIIs and ON cone bipolars was demonstrated by intracellular injection of Neurobiotin. In addition, extracellular recording in the knockout revealed the complete elimination of rod-mediated, on-center responses at the ganglion cell level. These data represent direct proof that electrical synapses are critical for the propagation of rod signals across the mammalian retina, and they demonstrate the existence of multiple rod pathways, each of which is dependent on electrical synapses.

Alkaline Phosphatase↗

PubMedDate not supplied

Residual photosensitivity in mice lacking both rod opsin and cone photoreceptor cyclic nucleotide gated channel 3 alpha subunit.

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 in Rho(-/-) Cnga3(-/-) mice. Moreover, these animals retain a pupil light reflex, photoentrainment, and light induction of the immediate early gene c-fos in 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 in Rho(-/-) Cnga3(-/-) mice. Thus, it seems that non-rod non-cone photoreceptors can drive many, but not all, non-image-forming light responses.

Animals↗

PubMed2005

GC1 deletion prevents light-dependent arrestin translocation in mouse cone photoreceptor cells.

PURPOSE: Light-driven translocation of phototransduction regulatory proteins between the inner and outer segments of photoreceptor cells plays a role in the adaptation of these cells to light. The purpose of this study was to examine the effects of the absence of guanylate cyclase 1 (GC1) on light-driven protein translocation in rod and cone cells. Both cell types express GC1, but differ in sensitivity, saturation, and response times to light. METHODS: Immunohistochemical techniques employing antibodies specific for cone and rod transducin alpha (Talpha) subunits and arrestins were used to examine light-driven translocation of these proteins in the retinas of wild-type and GC1 knockout (KO) mice. RESULTS: Translocation of cone arrestin from cone outer segments to the inner cell regions was disrupted in the absence of GC1, whereas translocation of arrestin and Talpha in rods was not affected. Cone Talpha did not translocate in wild-type and GC1 KO mice, but differed in its subcellular distribution in GC1 KO retina, remaining in the cone outer segment in light and in dark. CONCLUSIONS: These results suggest that multiple, independent pathways regulate the translocation of phototransduction proteins and that GC1, and presumably cGMP, are of key importance in signaling the translocation of cone arrestin.

Animals↗

PubMed2002

Crystal structure of rhodopsin: a template for cone visual pigments and other G protein-coupled receptors.

The crystal structure of rhodopsin has provided the first three-dimensional molecular model for a G-protein-coupled receptor (GPCR). Alignment of the molecular model from the crystallographic structure with the helical axes seen in cryo-electron microscopic (cryo-EM) studies provides an opportunity to investigate the properties of the molecule as a function of orientation and location within the membrane. In addition, the structure provides a starting point for modeling and rational experimental approaches of the cone pigments, the GPCRs in cone cells responsible for color vision. Homology models of the cone pigments provide a means of understanding the roles of amino acid sequence differences that shift the absorption maximum of the retinal chromophore in the environments of different opsins.

Amino Acid Sequence↗

PubMed2000

Parallel pathways for spectral coding in primate retina.

The primate retina is an exciting focus in neuroscience, where recent data from molecular genetics, adaptive optics, anatomy, and physiology, together with measures of human visual performance, are converging to provide new insights into the retinal origins of color vision. Trichromatic color vision begins when the image is sampled by short- (S), middle- (M) and long- (L) wavelength-sensitive cone photoreceptors. Diverse retinal cell types combine the cone signals to create separate luminance, red-green, and blue-yellow pathways. Each pathway is associated with distinctive retinal architectures. Thus a blue-yellow pathway originates in a bistratified ganglion cell type and associated interneurons that combine excitation from S cones and inhibition from L and M cones. By contrast, a red-green pathway, in which signals from L and M cones are opposed, is associated with the specialized anatomy of the primate fovea, in which the "midget" ganglion cells receive dominant excitatory input from a single L or M cone.

Animals↗