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PubMedDate not supplied

Probing inner retinal circuits in the rod pathway: a comparison of c-fos activation in mutant mice.

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 (Tr alpha-/-) 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.

Animals↗
PubMed2001

Rod-cone interactions: developmental and clinical significance.

During the last decade, numerous research reports have considerably improved our knowledge about the physiopathology of retinal degenerations. Three non-mutually exclusive general areas dealing with therapeutic approaches have been proposed; gene therapy, pharmacology and retinal transplantations. The first approach involving correction of the initial mutation, will need a great deal of time and further development before becoming a therapeutic tool in human clinical practice. The observation that cone photoreceptors, even those seemingly unaffected by any described anomaly, die secondarily to rod disappearance related to mutations expressed specifically in the latter, led us to study the interactions between these two photoreceptor populations to search for possible causal links between rod degeneration and cone death. These in vivo and in vitro studies suggest that paracrine interactions between both cell types exist and that rods are necessary for continued cone survival. Since the role of cones in visual perception is essential, pending the identification of the factors mediating these interactions underway, rod replacement by transplantation and/or neuroprotection by trophic factors or alternative pharmacological means appear as promising approaches for limiting secondary cone loss in currently untreatable blinding conditions.

Animals↗
PubMed1999

Role of nitric oxide in photoreceptor survival in embryonic chick retinal cell culture.

The presence of nitric oxide synthase (NOS) in chick retina during development has allowed us to study the role of nitric oxide (NO) during retinal differentiation in dissociated chick retinal cell culture from embryonic day 6. We have demonstrated the presence of nicotinamide adenine dinucleotide phosphate diaphorase staining in these cultures after 3 days in vitro (Div), with a maximal intensity after 8 Div, corresponding to embryonic day 14. Immunohistochemistry studies confirmed the presence of the two isoforms of NOS, NOS-I and -III, in dissociated retinal cell cultures at 8 Div. Addition of NG-monomethyl-L-arginine, a NOS inhibitor, to retinal cell cultures prevented NO production but did not modify the appearance and the survival of ganglion and amacrine cells. However, immunohistochemical analysis with distinct markers for photoreceptor cells (rods and cones) showed that inhibition of endogenous NOS in retinal cell cultures prevented the developmental decrease of rod number between 5 and 8 Div, thus supporting the hypothesis that NO may be involved in the cell death of rods during the development of the retina.

Animals↗
PubMed2007

Dynamic expression of the basic helix-loop-helix transcription factor neuroD in the rod and cone photoreceptor lineages in the retina of the embryonic and larval zebrafish.

NeuroD is a basic helix-loop-helix (bHLH) transcription factor critical for determining neuronal cell fate and regulating withdrawal from the cell cycle. We showed previously that, in goldfish, neuroD is expressed in the rod photoreceptor lineage, and we inferred that neuroD is also expressed in a subset of amacrine cells and nascent cone photoreceptors. Here we extended that study by examining the temporal and spatial expression pattern of neuroD in the embryonic and larval zebrafish and by identifying the cell types that express this gene. NeuroD expression in the developing zebrafish retina is dynamic, spanning early retinogenesis and the maturation of cone photoreceptors. In early retinogenesis neuroD expression expands from a small patch in the ventronasal retina, through the remaining retinal neuroepithelium. As retinogenesis progresses, neuroD expression becomes restricted to amacrine cells, immature cones, and cells of rod and cone lineages. This expression achieves an adult pattern by 96 hours postfertilization (hpf), whereupon the temporal pattern of neuroD expression in central retina is spatially recapitulated at the germinative margin. The cellular pattern of expression suggests that neuroD regulates aspects of rod and cone genesis, but through separate cellular lineages. Furthermore, neuroD is coexpressed with the cone-rod-homeobox transcription factor (Crx) in putative cone progenitors and nascent cone photoreceptors, suggesting that, in the zebrafish retina, as in other vertebrate retinas, similar genetic cascades regulate photoreceptor genesis and maturation.

Animals↗
PubMed2003

Topography of photoreceptors and retinal ganglion cells in the spotted hyena (Crocuta crocuta).

The spatial distributions of photoreceptors and retinal ganglion cells were examined in the spotted hyena (Crocuta crocuta). Two populations of cones were identified by immunocytochemical labeling. The hyena retina contains approximately 2.3 million middle- to long-wavelength sensitive (M/L) cones that reach peak densities of about 7,500/mm(2) in the vicinity of the optic nerve head. A sparser population of short-wavelength sensitive (S) cones, totaling about 0.3 million, was also detected. There is a striking disparity in the spatial distributions of the two cone types with S cones achieving peak density in a region located well below the optic nerve head. The differences in the spatial distributions of the two cone types have implications both for visual sensitivity and for color vision. Hyena rods outnumber cones by about 100:1 with rod density falling off modestly along a central-peripheral gradient. Ganglion cells were identified in retinal wholemounts by Nissl staining patterns. Their distribution defines a prominent visual streak with highest spatial packing (approx. 4,200/mm(2)) in an area centralis that is located in the temporal retina. The total number of ganglion cells is estimated at about 260,000. Using standard assumptions the maximum spatial resolution of the spotted hyena is calculated to be about 8.4 cycles/degree, a value similar to estimates obtained for other terrestrial carnivores.

Animals↗
PubMed2003

Goalpha labels ON bipolar cells in the tiger salamander retina.

By using double-label immunocytochemistry and confocal microscopy, we studied rod and cone synaptic contacts, photoreceptor-bipolar cell convergence, and patterns of axon terminal ramification of ON bipolar cells in the tiger salamander retina. An antibody to recoverin, a calcium-binding protein found in photoreceptors and other retinal neurons in various vertebrates, differentially labeled rods and cones by lightly staining rod cell bodies, axons, and synaptic pedicles and heavily staining cone cell bodies and pedicles. An antibody to G(oalpha) labeled most ON bipolar cells, with axon terminals ramified mainly in strata 6-9 and a minor band in stratum 3 of the inner plexiform layer (IPL). Stratum 10 of the IPL was G(oalpha) negative, and previous studies showed that axon terminals of rod-dominated ON bipolar cells are monostratified in that stratum. The axonal morphology of G(oalpha)-positive cells resembled that of the cone-dominated (DBC(C)) or mixed rod and cone ON (DBC(M)) bipolar cells. The G(oalpha)-positive dendritic processes made close contact with all cone pedicles and superficial contact with some rod pedicles, consistent with the idea that G(oalpha) subunits are present in DBC(C)s and DBC(M)s. The size and density of these cells were analyzed, and their spatial distributions were determined. To our knowledge, this is the first study to characterize photoreceptor inputs and axon terminal morphology of a population of ON bipolar cell with the use of a G(oalpha) antibody as an immunomarker in the salamander retina.

Ambystoma↗
PubMed2005

Distinct patterns of expression of the RB gene family in mouse and human retina.

Although RB1 function is disrupted in the majority of human cancers, an undefined cell of developing human retina is uniquely sensitive to cancer induction when the RB1 tumor suppressor gene is lost. Murine retinoblastoma is initiated only when two of the RB family of genes, RB1 and p107 or p130, are inactivated. Although whole embryonic retina shows RB family gene expression by several techniques, when E14 developing retina was depleted of the earliest differentiating cells, ganglion cells, the remaining proliferating murine embryonic retinal progenitor cells clearly did not express RB1 or p130, while the longer splice form of p107 was expressed. Each retinal cell type expressed some member of the RB family at some stage of differentiation. Rod photoreceptors stained for the RB1 protein product, pRB, and p107 in only a brief window of postnatal murine development, with no detectable staining for any of the RB family proteins in adult human and mouse rod photoreceptors. Adult mouse and human Muller glia, ganglion and rare horizontal cells, and adult human, but not adult mouse, cone photoreceptors stained for pRB. The RB gene family is dynamically and variably expressed through retinal development in specific retinal cells.

Animals↗
PubMed2005

Cone function studied with flicker electroretinogram during progressive retinal degeneration in RCS rats.

The Royal College of Surgeons (RCS) rat has a primary defect in retinal pigment epithelial cells that leads to the progressive loss of photoreceptors and central visual responsiveness. While most rods are lost by 90 days of age (P90), cones degenerate more slowly, and can be detected anatomically up to 2 years of age, despite massive neuronal death and retinal remodelling. To examine how this progressive degenerative process impacts on cone function, we recorded the electroretingram to white light flashes (1.37 log cd s m(-2)) presented at frequencies ranging from 3 to 50 Hz, under light adapted conditions (29.8 cd m(-2)). Pigmented dystrophic and congenic non-dystrophic RCS rats aged from 18 to 300 days were studied. In all responsive animals at all ages, maximal amplitudes were obtained at 3 Hz. In both non-dystrophic and dystrophic rats, there was an increase from P18 to P21 in response amplitude and critical fusion frequency. After P21, these two parameters declined progressively with age in dystrophic rats. Other changes included prolongation in latency, which was first detected prior to the initiation of amplitude reduction. While phase shifts were also detected in dystrophic RCS rats, they appeared at later degenerative stages. The latest age at which responses could be elicited in dystrophic rats was at P200, with positive waves being replaced by negative deflections. The effect of increments in the intensity of background illumination was tested at P50 in both groups. This caused a diminution in flicker response amplitude and critical fusion frequencies in non-dystrophics, while in dystrophic animals, response amplitudes were reduced only at low frequencies and critical fusion frequencies were unaltered. In conclusion, although dystrophic RCS rats undergo a progressive decline in cone function with age, the flicker responsiveness at P21 is comparable to that of non-dystrophic congenic rats, suggesting normal developmental maturation of the cone system in this animal model of retinal degeneration. Flicker responses can be recorded up to P200, at which point the retina has undergone severe regressive and reactive changes in its connectivity patterns. The fact that responses at this age consist of solely negative deflections might be a reflection of the highly pathological state of the retina.

Aging↗
PubMed2001

Excess cone cell proliferation due to lack of a functional NR2E3 causes retinal dysplasia and degeneration in rd7/rd7 mice.

The rd7 mouse is a model for hereditary retinal degeneration characterized clinically by retinal spotting throughout the fundus and late onset retinal degeneration, and histologically by retinal dysplasia manifesting as folds and whorls in the photoreceptor layer. This study demonstrates that the rd7 phenotype results from a splicing error created by a genomic deletion of an intron and part of an exon. Hematoxylin/eosin staining of rd7 tissue shows that the whorls in the outer nuclear layer of the retina do not appear during embryonic development but manifest by postnatal day 12.5 (P12.5). Furthermore, in situ hybridization data indicates that the Nr2e3 message is first present at barely discernable levels at embryonic day 18.5, becomes abundant by P2.5, and reaches maximal adult levels by P10.5. Results from these experiments indicate that Nr2e3 message is expressed prior to the development of S-cones. This data coincides with studies in humans showing that mutations in Nr2e3 result in a unique type of retinal degeneration known as enhanced S-cone syndrome, where patients have a 30-fold increase in S-cone sensitivity compared to normal. Immunohistochemical staining of cone cells demonstrates that rd7 retinas have an increased number of cone cells compared to wild-type retinas. Thus, Nr2e3 may function by regulating genes involved in cone cell proliferation, and mutations in this gene lead to retinal dysplasia and degeneration by disrupting normal photoreceptor cell topography as well as cell-cell interactions.

Animals↗
PubMed2002

Cone neurite sprouting: an early onset abnormality of the cone photoreceptors in the retinal degeneration mouse.

PURPOSE: Mutations in many rod genes can cause inherited blinding neurodegeneration in the retina characterized by sequential death of rod and cone photoreceptors. This study was to examine the morphological changes of the cone photoreceptors in retinal degeneration (rd1) mice caused by rod-specific cGMP phosphodiesterase beta-subunit gene mutation and to gain insights into the early cellular events underlying the secondary cone death. METHODS: Transgenic mice that have their living cones labeled by the green fluorescent protein (GFP) transgene and carry the homozygous rd1 mutation were generated, and identified by PCR analysis of the mouse tail DNA and PCR coupled Dde I digestion. The morphology of cone cells in live and fixed retinas from developing and adult mice was examined with fluorescence and scanning laser confocal microscopy. Some fixed mouse retinas were also examined by immunocytochemical staining. Volume images from the confocal three-dimensional (3D) data sets were processed with IMARIS software for 3D view of the detailed cone cell morphology. RESULTS: The cone photoreceptors in the rd1 retinas exhibited a novel process of neurite sprouting, in addition to the general pathological changes of cone degeneration such as shortening and loss of cone outer and inner segments, and loss and death of the cones. The cones gave rise to prominent neurite outgrowth from their axons and synaptic pedicles as well. Most neurites had beaded varicosities along their length and some terminated as bulbous structures. Some cone pedicles showed abnormally elongating and branching processes. The degenerating cones were disorganized, and migrated into the inner nuclear layer. Some cone neurites extended horizontally and appeared to contact the rod bipolar cells, while others projected into the inner plexiform layer. The aberrant cone sprouting started from P8 when rod degeneration generally began, and became evident by P10. In contrast, this abnormal cone neurite sprouting was not observed in the examined control mice that did not carry the rd1 mutation. Double-labeling with cone cell-specific peanut agglutinin confirmed that the fluorescent cells expressing the GFP in the rd1 retinas were indeed the cone photoreceptors. CONCLUSIONS: Cone photoreceptors in the rd1 mice underwent a remarkable process of neurite sprouting that appeared to start before the onset of cone cell death and persisted throughout the course of cone degeneration. This novel process of cone neurite sprouting may be a part of the early cellular events leading to the cone photoreceptor death in retinal degeneration of the rd1 mice.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2001

Photoreceptor plasticity in reaggregates of embryonic chick retina: rods depend on proximal cones and on tissue organization.

Plasticity of photoreceptors and their integration into epithelial structures homologous to an outer nuclear layer (ONL), was investigated in embryonic chick retinal cell reaggregates by immunohistochemistry using an antibody specific for red plus green cones (RG-cones) and an antibody for rods. If reaggregates are raised in the presence of pigmented epithelium (RPE), completely reconstructed, stratified retinal spheres are produced, where all rods and cones are integrated into an outer laminar ONL, similar to a normal retina. In the absence of RPE, 'rosetted' spheres form which contain internal rosettes homologous to an ONL. Only a minor fraction of cones and rods of 'rosetted' spheres are located within rosettes, while a larger fraction is diffusely displaced in nonorganized areas, thus, not contributing to an ONL-like epithelium. In both types of spheres, the total percentage of RG-cones was similar to the in vivo retina, indicating that expression of cones is autonomous. Following cones, after about one day, rods developed only within already existing RG-cone clusters. Thereby, the ratio of rods to RG-cones increases as the tissue organization decreases: for stratified spheres this ratio is, 0.50 (1 rod/2 cones; similar to mature retina); for rosettes, 0.74 (3 rods/4 cones) and for nonorganized areas, 1.09 (1 rod/1 cone) -- a higher ratio under our conditions has never been detected. Thus, rod expression depends strictly on the presence of nearby cones; their relative numbers are distinctively adjusted according to the cytoarchitecture of the tissue environment. The biomedical implications of these findings are briefly discussed.

Animals↗
PubMed2004

Recruitment of the rod pathway by cones in the absence of rods.

In mammalian retinas, rods and cones connect to distinct sets of bipolar cells. In the retina of Nrl (neural retina leucine zipper) knock-out mice, in which rods fail to form and all photoreceptors are cones, rod bipolar cells have normal morphology, pattern of staining, and lamination, but they form synaptic connections with cones. Hence, retinal interneurons are not entirely committed to the choice of their synaptic partners; also, their morphology and pattern of distribution of their processes in the synaptic layers of the retina are not instructed by the establishment of synaptic connections with cognate photoreceptor(s). These findings are of considerable relevance for our understanding of mechanisms responsible for cell recognition during development and in the context of using transplanted tissue to restore vision in retinal degeneration.

Animals↗
PubMed1998

Fine structure of the retinal photoreceptors of the emu (Dromaius novaehollandiae).

The retinal photoreceptors of the emu (Dromaius novaehollandiae) consist of rods, single cones and double (unequal) cones present in a ratio of about 10:1:4 respectively. The rods are long slender cells which are felt to undergo retinomotor movements. The rod outer segment is a stack of bimembranous discs which display shallow peripheral incisures and are all of the same diameter. The rod inner segment displays an ellipsoid of mitochondria, much rough endoplasmic reticulum (ER), numerous polysomes and a prominent hyperboloid of glycogen. Single cones show a tapered outer segment, no oil droplet but a large ellipsoid with several small lipid droplets and a paraboloid of glycogen. Double cones consist of a chief member which displays a single large heterogeneous oil droplet and no paraboloid, and an accessory cone which has no oil droplet but again several small lipid droplets and a large paraboloid. All cones show a large ellipsoid, plentiful polysomes, rough ER, Golgi zones and autophagic vacuoles. Along the length of the contiguous membranes of the two members of the double cones are scattered membrane densifications. The cones are not believed to undergo retinomotor movements in the emu. Rod photoreceptors are relatively small in diameter and hence are closely packed, while the larger cones are not as abundant. Rods and cones (both types) display both invaginated (ribbon) synapses as well as numerous superficial (conventional) synaptic sites.

Animals↗
PubMed1999

Biochemical analysis of a dimerization domain mutation in RetGC-1 associated with dominant cone-rod dystrophy.

Mutations in the photoreceptor membrane guanylyl cyclase RetGC-1 have been linked to autosomal dominant cone-rod dystrophy. Three mutations were identified that alter strictly conserved residues within the RetGC-1 dimerization domain, a region predicted to form an amphipathic alpha-helical coil. Here we report on a biochemical characterization of one of the mutations, a substitution of cysteine for arginine at residue 838. We generated this mutation in vitro and measured its catalytic activity and sensitivity to guanylyl cyclase activating protein 1 (GCAP-1) and GCAP-2. The R838C substitution has several effects. It reduces the overall catalytic ability of RetGC-1 and dramatically reduces stimulation by GCAP-2, although GCAP-2 still appears to interact with the protein. The R838C substitution also increases the apparent affinity of RetGC-1 for GCAP-1 and alters the Ca(2+) sensitivity of the GCAP-1 response, allowing the mutant to be stimulated by GCAP-1 at higher Ca(2+) concentrations than wild type. The diminished response to GCAP-2, which we propose is not likely the cause of cone-rod degeneration in these patients, is interesting mechanistically because it separates the ability to bind a specific GCAP from the ability to be stimulated by it, and it also discriminates between the mechanisms of activation of GCAP-1 vs. GCAP-2. We suggest that the gain-of-function effects of R838C on RetGC-1 stimulated by GCAP-1, which are dominant in vitro and may cause an abnormal increase in cGMP synthesis in dark-adapted photoreceptors, may be the cause of the cone-rod degeneration.

Amino Acid Sequence↗
PubMed2004

Longitudinal diffusion in retinal rod and cone outer segment cytoplasm: the consequence of cell structure.

Excitation signals spread along photoreceptor outer segments away from the site of photon capture because of longitudinal diffusion of cGMP, a cytoplasmic second messenger. The quantitative features of longitudinal diffusion reflect the anatomical structure of the outer segment, known to be profoundly different in rod and cone photoreceptors. To explore how structural differences affect cytoplasmic diffusion and to assess whether longitudinal diffusion may contribute to the difference in signal transduction between photoreceptor types, we investigated, both theoretically and experimentally, the longitudinal diffusion of small, hydrophilic molecules in outer segments. We developed a new theoretical analysis to explicitly compute the longitudinal diffusion constant, Dl, in terms of outer segment structure. Using time-resolved fluorescence imaging we measured Dl of Alexa488 and lucifer yellow in intact, single cones and validated the theoretical analysis. We used numerical simulations of the theoretical model to investigate cGMP diffusion in outer segments of various species. At a given time interval, cGMP spreads further in rod than in cone outer segments of the same dimensions. Across all species, the spatial spread of cGMP at the peak of the dim light photocurrent is 3-5 microm in rod outer segments, regardless of their absolute size. Similarly the cGMP spatial spread is 0.7-1 microm in cone outer segments, independently of their dimensions.

Animals↗
PubMed1997

Age-related distribution of cones and ON-bipolar cells in the rd mouse retina.

PURPOSE: Retinal dystrophic (rd) mice lose most of their rod photoreceptors within the first three weeks after birth. We determined the age-related distribution of peanut agglutinin lectin (PNA)-labeled cones during the first 12 months of age. We also investigated whether the density of ON-bipolar cells expressing L7 protein was affected by their loss of photoreceptor inputs. METHODS: rd mice were selected from a transgenic strain which expresses an L7-beta-galactosidase fusion gene localized to ON-bipolar cells. Cones were stained with PNA and ON-bipolar cells with bluo-gal (halogenated indolyl-beta-D-galactoside). Retinas were flat-mounted and observed at 1, 2, 3, 6 and 12 months of age. RESULTS: PNA-labeled cones are distributed unevenly across the retina at 1 month postnatal. Their concentration decreases first in the central and far peripheral retina, leaving a ring of labeled cells in the midperipheral region. At 3 months, a larger patch of cones remains in the supero-temporal midperipheral region and a smaller patch in the infero-nasal retina. By 6 months, few cones remain in the infero-nasal retina; by 1 year approximately 100 cones remain in the entire retina, localized to the superior midperipheral region. ON-bipolar cells appear evenly distributed at 1 month. By 2-3 months, relatively more bluo-gal staining is seen in the midperipheral regions underlying dense cone populations. At 6-12 months, bluo-gal label is distributed in a spotty pattern with little or no staining seen in areas of apparent neovascularization. CONCLUSIONS: (1) PNA-labeling of cones in the rd retina deteriorates in a distinct spatial pattern with the longest cone survival in the midperipheral superior retina. (2) ON-bipolar cells are more densely labeled in regions of high cone density during the early months of cone degeneration and, in later stages, show relative decreases in regions of apparent neovascularization.

Age Factors↗