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PubMed2004

Cytokine-induced activation of signal transducer and activator of transcription in photoreceptor precursors regulates rod differentiation in the developing mouse retina.

Ciliary neurotrophic factor (CNTF) exhibits multiple biological effects during vertebrate retinogenesis, including regulation of photoreceptor cell differentiation. In the early postnatal mouse retina, CNTF induces rapid and transient phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT3 and the extracellular signal-regulated kinase (ERK). Although both proliferating progenitor cells and postmitotic neurons respond directly to cytokine signals, CNTF elicits distinct phosphorylation patterns of STAT3 and ERK. CNTF stimulation induces low levels of STAT3 phosphorylation in progenitors and differentiated neurons but a robust STAT3 activation among postmitotic photoreceptor precursors expressing the cone-rod homeobox gene Crx and newly differentiated rod photoreceptors. In contrast, CNTF causes preferential phosphorylation of ERK in progenitor cells and photoreceptor precursors. Inhibition of the cytokine receptor gp130 using neutralizing antibodies reveals that gp130 is required for both CNTF-induced STAT3 and ERK phosphorylation. Perturbation of STAT signaling by a STAT inhibitor peptide or a dominant-negative STAT3 mutant causes enhanced production of rod photoreceptors in the absence of exogenous cytokines, whereas inhibiting ERK activation by a MEK (mitogen-activated protein kinase kinase)-specific inhibitor has no effect on rod photoreceptor differentiation in vitro. Furthermore, disrupting the function of epidermal growth factor (EGF) receptors, which modulate rod development in vivo, indicates that the EGF family of ligands does not mediate the inhibitory effect of cytokine on rod differentiation. These results demonstrate that cytokine signal transduction is dynamic and heterogeneous in the developing retina, and that endogenous ligand-induced STAT activation in retinal progenitor and/or photoreceptor precursor cells plays an important role in regulating photoreceptor development.

Animals↗

PubMed1994

Effect of photoregeneration on the calculation of the amount of rhodopsin bleached by small flashes.

A sample of rhodopsin that is exposed to a series of small light flashes of equal intensity is expected to bleach in successively smaller decrements in proportion to the remaining unbleached rhodopsin. The exponential depletion law describing this effect has been used as a rapid, convenient, and intuitive method for determining the fraction of rhodopsin bleached per flash. This method is commonly assumed to be free of error provided the amount bleached is small, so that there is no significant photoregeneration. We show here, however, that if there is any photoregeneration, the bleach fraction calculated in this manner can be in error by a factor of two or more, no matter how little rhodopsin is bleached. This flaw occurs insidiously, without perturbing the expected exponentiality of the bleaching decrements, thereby escaping ready notice. The erroneous bleach values readily propagate as underestimates of metarhodopsin and accompanying G-protein equilibrium and kinetic constants. We derive equations for correcting such errors and illustrate how empirical constants can be obtained from experiments that permit the true fraction bleached to be determined.

Animals↗

PubMed2001

A photic visual cycle of rhodopsin regeneration is dependent on Rgr.

During visual excitation, rhodopsin undergoes photoactivation and bleaches to opsin and all-trans-retinal. To regenerate rhodopsin and maintain normal visual sensitivity, the all-trans isomer must be metabolized and reisomerized to produce the chromophore 11-cis-retinal in biochemical steps that constitute the visual cycle and involve the retinal pigment epithelium (RPE; refs. 3-8). A key step in the visual cycle is isomerization of an all-trans retinoid to 11-cis-retinol in the RPE (refs. 9-11). It could be that the retinochrome-like opsins, peropsin, or the retinal G protein-coupled receptor (RGR) opsin12-16 are isomerases in the RPE. In contrast to visual pigments, RGR is bound predominantly to endogenous all-trans-retinal, and irradiation of RGR in vitro results in stereospecific conversion of the bound all-trans isomer to 11-cis-retinal. Here we show that RGR is involved in the formation of 11-cis-retinal in mice and functions in a light-dependent pathway of the rod visual cycle. Mutations in the human gene encoding RGR are associated with retinitis pigmentosa.

Animals↗

PubMed1996

Development of photoreceptor mosaics in the primate retina.

The mosaic of rods and cones in the primate retina is the neuronal array where the visual world is first mapped onto the central nervous system. Rods, which mediate scotopic vision, and cones, which mediate photopic and color vision, are found in all vertebrate species. However, regional differences in the topographic arrangement and ratio of rods to cones vary dramatically among species, including different primates. Furthermore, the proportion and distribution of the wavelength-sensitive cone subtypes vary considerably between primates that occupy different visual habitats. What genetic or environmentally regulated mechanisms specify the position, phenotype, and ratios of photoreceptor subtypes? Available data suggest that the transient appearance of early-differentiating cones may serve to delineate basic species-specific retinal coordinates and determine the opsin phenotype of local assemblies of cones in the fetal photoreceptor mosaic. This article will summarize presently available data and our ideas of how the photoreceptor mosaic is organized in the adult primate retina, the features of these mosaics, which vary between primate species, and the developmental mechanisms, which may account for the emergence of photoreceptor position and specification of their phenotypes in the primate retina.

Animals↗

PubMed2005

The rod photoreceptor pattern is set at the optic vesicle stage and requires spatially restricted cVax expression.

How and when positional identities in the neural retina are established have been addressed primarily with respect to the topographic projections of retinal ganglion cells onto their targets in the brain. Although retinotectal map formation is a prominent manifestation of retinal patterning, it is not the only one. Photoreceptor subtypes are arranged in distinct, species-specific patterns. The mechanisms used to establish photoreceptor patterns have been relatively unexplored at the mechanistic level. We performed ablations of the eye anlage in chickens and found that removal of the anterior or dorsal optic vesicle caused loss of the area centralis, which is a rod-free central area of the retina, and severely disorganized other aspects of the rod pattern. These observations indicate that the anteroposterior and dorsoventral distribution of rods is determined by the optic vesicle stage. To investigate the molecular mechanisms involved, the rod distribution was analyzed after viral misexpression of several patterning genes that were previously shown to be important in positional specification of retinal ganglion cells. Ectopic expression of FoxG1, SOHo1,or GH6 transcription factors expressed in the anterior optic vesicle and/or optic cup, respectively, did not affect the rod pattern. This pattern therefore appears to be specified by an activity acting before, or in parallel with, these factors. In contrast, misexpression of the ventrally restricted transcription factor, cVax, severely disturbed the rod pattern.

Animals↗

PubMed2003

Calcium/calmodulin modulation of olfactory and rod cyclic nucleotide-gated ion channels.

Cyclic nucleotide-gated (CNG) ion channels mediate sensory transduction in olfactory sensory neurons and retinal photoreceptor cells. In these systems, internal calcium/calmodulin (Ca2+/CaM) inhibits CNG channels, thereby having a putative role in sensory adaptation. Functional differences in Ca2+/CaM-dependent inhibition depend on the different subunit composition of olfactory and rod CNG channels. Recent evidence shows that three subunit types (CNGA2, CNGA4, and CNGB1b) make up native olfactory CNG channels and account for the fast inhibition of native channels by Ca2+/CaM. In contrast, two subunit types (CNGA1 and CNGB1) appear sufficient to mirror the native properties of rod CNG channels, including the inhibition by Ca2+/CaM. Within CNG channel tetramers, specific subunit interactions also mediate Ca2+/CaM-dependent inhibition. In olfactory CNGA2 channels, Ca2+/CaM binds to an N-terminal region and disrupts an interaction between the N- and C-terminal regions, causing inhibition. Ca2+/CaM also binds the N-terminal region of CNGB1 subunits and disrupts an intersubunit, N- and C-terminal interaction between CNGB1 and CNGA1 subunits in rod channels. However, the precise N- and C-terminal regions that form these interactions in olfactory channels are different from those in rod channels. Here, we will review recent advances in understanding the subunit composition and the mechanisms and roles for Ca2+/CaM-dependent inhibition in olfactory and rod CNG channels.

Amino Acid Sequence↗

PubMed2004

The extracellular matrix component WIF-1 is expressed during, and can modulate, retinal development.

We have shown previously that components of the extracellular matrix (ECM) modulate neuronal development. Here, we searched for additional ECM elements that might play roles in retinal histogenesis and identified a secreted glycoprotein that is heavily expressed in the retina. This molecule, named by others Wnt Inhibitory Factor-1 (WIF-1), is expressed during and after the period of rod photoreceptor morphogenesis in the mouse. We show that a potential WIF-1 ligand, Wnt4, as well as a potential Wnt4 receptor, fzd4, and a potential Wnt4 coreceptor, LRP6, are expressed in the region of, and at the time of, rod photoreceptor genesis. WIF-1 and Wnt4 are coexpressed during retinal development and bind to each other; therefore, they are likely to interact during rod production. WIF-1 protein inhibits rod production, and anti-WIF-1 antibodies increase rod production; in contrast, Wnt4 promotes rod production. Together, these data suggest that WIF-1 and Wnt4, both components of the ECM, regulate mammalian photoreceptor development.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

Transgenic expression of a GFP-rhodopsin COOH-terminal fusion protein in zebrafish rod photoreceptors.

To facilitate the identification and characterization of mutations affecting the retina and photoreceptors in the zebrafish, a transgene expressing green fluorescent protein (GFP) fused to the C-terminal 44 amino acids of Xenopus rhodopsin (Tam et al., 2000) under the control of the 1.3-kb proximal Xenopus opsin promoter was inserted into the zebrafish genome. GFP expression was easily observed in a ventral patch of retinal cells at 4 days postfertilization (dpf). Between 45-50% of the progeny from the F1, F2, and F3 generations expressed the transgene, consistent with a single integration event following microinjection. Immunohistochemical analysis demonstrated that GFP is expressed exclusively in rod photoreceptors and not in the UV, blue, or red/green double cones. Furthermore, GFP is localized to the rod outer segments with little to no fluorescence in the rod inner segments, rod cell bodies, or rod synapse regions, indicating proper targeting and transport of the GFP fusion protein. Application of exogenous retinoic acid (RA) increased the number of GFP-expressing cells throughout the retina, and possibly the level of expressed rhodopsin. When bred to a zebrafish rod degeneration mutant, fewer GFP-expressing rods were seen in living mutants as compared to wild-type siblings. This transgenic line will facilitate the search for recessive and dominant mutations affecting rod photoreceptor development and survival as well as proper rhodopsin expression, targeting, and transport.

Amblyopia↗

PubMed1997

Localization of dystrophin and beta-dystroglycan in bovine retinal photoreceptor processes extending into the postsynaptic dendritic complex.

Dystrophin is an actin-binding protein of the membrane cytoskeleton that binds to dystroglycan, an integral membrane protein of the plasma membrane that is posttranslationally cleaved into a transmembrane dystrophin-binding beta-moiety and an extracellular laminin- and agrin-binding alpha-moiety. Mutations of dystrophin may not only cause Duchenne muscular dystrophy but may also be associated with abnormal electroretinograms assumed to result from disturbed neurotransmission between retinal photoreceptors and bipolar cells. Here we show by confocal laser microscopy and immunogold electron microscopy that dystrophin and beta-dystroglycan are colocalized in bovine rod photoreceptor synaptic complexes distal from the ribbon-containing active synaptic zones. Both proteins are restricted to a microdomain of the photoreceptor plasma membrane that forms the lateral wall of the synaptic cavity and projects with finger-like extensions into the postsynaptic dendritic complex. Within the cavity these processes eventually come into close contact with bipolar cell dendritic endings. We speculate that the dystrophin-dystroglycan complex of the cavital plasma membrane stabilizes the elaborate synaptic morphology or plays a role in the immobilization of still unknown transporters and receptors involved in certain aspects of neurotransmission to bipolar cells. A further outcome of this study is that dystrophin and dystroglycan are located along the vitread membrane surface of Müller cell endfeet where this protein complex may be important for the attachment of the retina to the basal lamina and the vitreous.

Animals↗

PubMed2000

Lead and calcium produce rod photoreceptor cell apoptosis by opening the mitochondrial permeability transition pore.

Calcium overload is suggested to play a fundamental role in the process of rod apoptosis in chemical-induced and inherited retinal degenerations. However, this hypothesis has not been tested directly. We developed an in vitro model utilizing isolated rat retinas to determine the mechanisms underlying Ca(2+)- and/or Pb(2+)-induced retinal degeneration. Confocal microscopy, histological, and biochemical studies established that the elevated [Ca(2+)] and/or [Pb(2+)] were localized to photoreceptors and produced rod-selective apoptosis. Ca(2+) and/or Pb(2+) induced mitochondrial depolarization, swelling, and cytochrome c release. Subsequently caspase-9 and caspase-3 were sequentially activated. Caspase-7 and caspase-8 were not activated. The effects of Ca(2+) and Pb(2+) were additive and blocked completely by the mitochondrial permeability transition pore (PTP) inhibitor cyclosporin A, whereas the calcineurin inhibitor FK506 had no effect. The caspase inhibitors carbobenzoxy-Leu-Glu-His-Asp-CH(2)F and carbobenzoxy-Asp-Glu-Val-Asp-CH(2)F, but not carbobenzoxy-Ile-Glu-Thr-Asp-CH(2)F, differentially blocked post-mitochondrial events. The levels of reduced and oxidized glutathione and pyridine nucleotides in rods were unchanged. Our results demonstrate that rod mitochondria are the target site for Ca(2+) and Pb(2+). Moreover, they suggest that Ca(2+) and Pb(2+) bind to the internal metal (Me(2+)) binding site of the PTP and subsequently open the PTP, which initiates the cytochrome c-caspase cascade of apoptosis in rods.

Animals↗

PubMed1995

Changes in retinal cell fate induced by overexpression of EGF receptor.

The differentiation of multipotential progenitor cells in the vertebrate retina into photoreceptors, neurons and glial cells is regulated in part by cell-cell signalling. Transforming growth factor (TGF)-alpha is one of the extracellular signals implicated in the control of several aspects of retinal development, including proliferation and cell fate. The way cells interpret pleiotropic signals such as TGF-alpha is influenced by the level of expression of epidermal growth factor receptor (EGF-R) in some cell lines. To address the influence of receptor level on responses of retinal progenitor cells to TGF-alpha, additional copies of EGF-Rs were introduced in vitro and in vivo with a retrovirus. Normally in vitro, low concentrations of TGF-alpha stimulated proliferation whereas high concentrations biased choice of cell fate, inhibiting differentiation into rod photoreceptors while promoting differentiation into Müller glial cells. We report here that introduction of extra EGF-Rs into progenitor cells in vitro reduced the concentration of TGF-alpha required for changes in rod and Müller cell differentiation but did not enhance proliferation. Introduction of extra EGF-Rs in vivo increased the proportion of clones that contained Müller glial cells, suggesting that receptor level is normally limiting. These findings demonstrate that responsiveness to extracellular signals during development can be modulated by the introduction of additional receptors, and suggest that the level of expression of receptors for these signals contributes to the regulation of cell fate.

Animals↗

PubMed1993

Continued search for the cellular signals that regulate regeneration of dopaminergic neurons in goldfish retina.

Intraocular injections of low doses (0.7-1.4 mM estimated intraocular concentration) of 6-hydroxydopamine (6OHDA) selectively destroy dopaminergic neurons in the inner nuclear layer (INL) of goldfish retina, and they never regenerate. However, injection of a higher dose of 6OHDA (2.9 mM) destroys > 30% (but not all) of the cells in both the INL and the outer nuclear layer (ONL), but within 3 weeks, neurons in both the INL (including dopaminergic neurons) and the ONL regenerate. We hypothesize that the regenerated neurons derive from mitotic rod precursors in the ONL and that damage to the surrounding micro-environment (i.e. destruction of photoreceptors) triggers the regenerative response. To directly test this hypothesis, we selectively ablated > 99% of dopaminergic neurons (with low doses of 6OHDA) and up to 55% of rod photoreceptors (with tunicamycin), and asked whether the dopaminergic neurons regenerated, as evidenced by double immunolabeling with anti-tyrosine hydroxylase and anti-bromodeoxyuridine. After 38 days, the number of bromodeoxyuridine-immunoreactive rod nuclei was increased 2.4-fold compared to controls, but no regenerated dopaminergic neurons were found. These data suggest that although the rate of rod production increases, rod precursors do not alter their normal pathway of development to replace dopaminergic neurons in the INL when damage to the ONL is limited to destruction of rods.

Animals↗

PubMed1995

The rod pathway of the macaque monkey retina: identification of AII-amacrine cells with antibodies against calretinin.

AII-amacrine cells were characterized from Golgi-stained sections and wholemounts of the macaque monkey retina. Similar to other mammalian retinae, they are narrow-field, bistratified amacrine cells with lobular appendages in the outer half of the inner plexiform layer (IPL) and a bushy, smoother dendritic tree in the inner half. AII cells of the monkey retina were stained immunocytochemically with antibodies against the calcium-binding protein calretinin. Their retinal mosaic was elaborated, and their density distribution across the retina was measured. Convergence within the rod pathway was calculated. Electron microscopy of calretinin-immunolabelled sections was used to study the synaptic connections of the AII cells. They receive a major input from rod bipolar cells, and their output is largely onto cone bipolar cells. Thus, the rod pathway of the primate retina follows the general mammalian scheme as it is known from the cat, the rabbit, and the rat retina. The spatial sampling properties of macaque AII-amacrine cells are discussed and related to human scotopic visual acuity.

Animals↗

PubMed1998

The rod cGMP phosphodiesterase delta subunit dissociates the small GTPase Rab13 from membranes.

Small Rab GTPases are involved in the regulation of membrane trafficking. They cycle between cytosolic and membrane-bound forms. These membrane association/dissociation are tightly controlled by regulatory proteins. To search for proteins interacting with Rab13, a small GTPase associated with vesicles in fibroblasts and predominantly with tight junctions in epithelial cells, we screened a HeLa two-hybrid cDNA library and isolated a clone encoding a protein of 17.4 kDa. This protein, almost identical to the bovine rod cGMP phosphodiesterase delta subunit, was named human delta-PDE. The delta-PDE binds specifically to Rab13. It exhibits two putative C-terminal sequences necessary for the interaction with PDZ (PSD95, Dlg, ZO-1) domains contained in many proteins localized to specific plasma membrane microdomains. Immunofluorescence microscopic studies revealed that the vesicular stomatitis virus (VSV)-tagged delta-PDE is localized in vesicular structures accumulated near the plasma membrane in epithelial cells. Deletion of the PDZ binding motifs impair VSV-delta-PDE subcellular distribution. Purified recombinant delta-PDE had the capacity to dissociate Rab13 from cellular membranes. Our data support the proposal that delta-PDE, but not GDP dissociation inhibitor, may serve to control the dynamic of the association of Rab13 with cellular membranes.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed1999

Physiological and molecular characterization of the Na+/Ca2+ exchanger in human platelets.

In this report, we have demonstrated that Na+/Ca2+ exchanger activity in a human megakaryocytic cell line (CHRF-288 cells) is K+ dependent, similar to the properties previously described for Na+/Ca2+ exchange activity in human platelets. With the use of RT-PCR techniques and mRNA, the exchanger expressed in CHRF-288 cells was found to be identical to that expressed in human retinal rods. Northern blot analysis of the mRNA for the human retinal rod exchanger in CHRF-288 cells revealed a major transcript at 5.8 kb with two minor bands at 4.9 and 6.8 kb. mRNA for the retinal rod exchanger was also identified in human platelets. Using Ba2+ influx as a measure of Na+/Ca2+ exchange activity in human platelets, we have demonstrated that exchange activity is driven by the transmembrane gradient for K+ as well as that for Na+. We propose that the K+ dependence of the platelet Na+/Ca2+ exchanger could make platelets especially sensitive to daily fluctuations in salt intake.

Blood Platelets↗

PubMed1998

Variation in sensitivity, absorption and density of the central rod distribution with eccentricity.

PURPOSE: To assess the human rod photopigment distribution and sensitivity with high spatial resolution within the central +/-15 degrees and to compare the results of pigment absorption, sensitivity and rod density distribution (number of rods per square degree). METHOD: Rod photopigment density distribution was measured with imaging densitometry using a modified Rodenstock scanning laser ophthalmoscope. Dark-adapted sensitivity profiles were measured with green stimuli (17' arc diameter, 1 degrees spacing) using a T ubingen manual perimeter. Sensitivity profiles were plotted on a linear scale and rod photopigment optical density distribution profiles were converted to absorption profiles of the rod photopigment layer. RESULTS: Both the absorption profile of the rod photopigment and the linear sensitivity profile for green stimuli show a minimum at the foveal center and increase steeply with eccentricity. The variation with eccentricity corresponds to the rod density distribution. CONCLUSION: Rod photopigment absorption profiles, retinal sensitivity profiles, and the rod density distribution are linearly related within the central +/-15 degrees. This is in agreement with theoretical considerations. Both methods, imaging retinal densitometry using a scanning laser ophthalmoscope and dark-adapted perimetry with small green stimuli, are useful for assessing the central rod distribution and sensitivity. However, at present, both methods have limitations. Suggestions for improving the reliability of both methods are given.

Absorption↗

PubMed2006

Calcium-induced calcium release in rod photoreceptor terminals boosts synaptic transmission during maintained depolarization.

We examined the contribution of calcium-induced calcium release (CICR) to synaptic transmission from rod photoreceptor terminals. Whole-cell recording and confocal calcium imaging experiments were conducted on rods with intact synaptic terminals in a retinal slice preparation from salamander. Low concentrations of ryanodine stimulated calcium increases in rod terminals, consistent with the presence of ryanodine receptors. Application of strong depolarizing steps (-70 to -10 mV) exceeding 200 ms or longer in duration evoked a wave of calcium that spread across the synaptic terminals of voltage-clamped rods. This secondary calcium increase was blocked by high concentrations of ryanodine, indicating it was due to CICR. Ryanodine (50 microm) had no significant effect on rod calcium current (I(ca)) although it slightly diminished rod light-evoked voltage responses. Bath application of 50 microm ryanodine strongly inhibited light-evoked currents in horizontal cells. Whether applied extracellularly or delivered into the rod cell through the patch pipette, ryanodine (50 microm) also inhibited excitatory post-synaptic currents (EPSCs) evoked in horizontal cells by depolarizing steps applied to rods. Ryanodine caused a preferential reduction in the later portions of EPSCs evoked by depolarizing steps of 200 ms or longer. These results indicate that CICR enhances calcium increases in rod terminals evoked by sustained depolarization, which in turn acts to boost synaptic exocytosis from rods.

Animals↗

PubMed2001

Nrl and Sp nuclear proteins mediate transcription of rod-specific cGMP-phosphodiesterase beta-subunit gene: involvement of multiple response elements.

cGMP-phosphodiesterase (PDE) is the key effector in rod photoreceptor signal transduction. Mutations in the gene encoding its catalytic beta-subunit (beta-PDE) cause retinal degenerations leading to blindness. We report that the short -93 to +53 sequence in the upstream region of this gene is sufficient for beta-PDE transcription in both Y79 human retinoblastoma cells and Xenopus embryo heads maintained ex vivo. This sequence also functions as a minimal rod-specific promoter in transgenic Xenopus tadpoles. The Nrl transcription factor binds in vitro to the betaAp1/NRE regulatory element located within this region and transactivates it when overexpressed in nonretinal 293 embryonic kidney cells. We also found a G/C-rich activator element, beta/GC, important for promoter activity in Y79 retinoblastoma cells and Xenopus embryos. Both the ubiquitous Sp1 and the central nervous system-specific Sp4 transcription factors are expressed in retina and interact with this element in vitro. Electrophoretic mobilities of beta/GC-Y79 nuclear protein complexes are altered by antibodies against Sp1 and Sp4. Thus, our results implicate Nrl, Sp1, and Sp4 in transcriptional regulation of the rod-specific minimal beta-PDE promoter. We also conclude that Xenopus laevis is an efficient system for analyzing the human beta-PDE promoter and may be used to study other human retinal genes ex vivo and in vivo.

3',5'-Cyclic-GMP Phosphodiesterases↗