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Adaptive evolution of color vision genes in higher primates.
The intron 4 sequences of the three polymorphic alleles at the X-linked color photo-pigment locus in the squirrel monkey and the marmoset reveal that the alleles in each species are exceptionally divergent. The data further suggest either that each triallelic system has arisen independently in these two New World monkey lineages, or that in each species at least seven deletions and insertions (14 in the two species) in intron 4 have been transferred and homogenized among the alleles by gene conversion or recombination. In either case, the alleles in each species apparently have persisted more than 5 million years and probably have been maintained by overdominant selection.
The chemistry of John Dalton's color blindness.
John Dalton described his own color blindness in 1794. In common with his brother, he confused scarlet with green and pink with blue. Dalton supposed that his vitreous humor was tinted blue, selectively absorbing longer wavelengths. He instructed that his eyes should be examined after his death, but the examination revealed that the humors were perfectly clear. In experiments presented here, DNA extracted from his preserved eye tissue showed that Dalton was a deuteranope, lacking the middlewave photopigment of the retina. This diagnosis is shown to be compatible with the historical record of his phenotype, although it contradicts Thomas Young's belief that Dalton was a protanope.
Violet and blue light blocking intraocular lenses: photoprotection versus photoreception.
AIM: To analyse how intraocular lens (IOL) chromophores affect retinal photoprotection and the sensitivity of scotopic vision, melanopsin photoreception, and melatonin suppression. METHODS: Transmittance spectra of IOLs, high pass spectral filters, human crystalline lenses, and sunglasses are used with spectral data for acute ultraviolet (UV)-blue photic retinopathy ("blue light hazard" phototoxicity), aphakic scotopic luminous efficiency, melanopsin sensitivity, and melatonin suppression to compute the effect of spectral filters on retinal photoprotection, scotopic sensitivity, and circadian photoentrainment. RESULTS: Retinal photoprotection increases and photoreception decreases as high pass filters progressively attenuate additional short wavelength light. Violet blocking IOLs reduce retinal exposure to UV (200-400 nm) radiation and violet (400-440 nm) light. Blue blocking IOLs attenuate blue (440-500 nm) and shorter wavelength optical radiation. Blue blocking IOLs theoretically provide better photoprotection but worse photoreception than conventional UV only blocking IOLs. Violet blocking IOLs offer similar UV-blue photoprotection but better scotopic and melanopsin photoreception than blue blocking IOLs. Sunglasses provide roughly 50% more UV-blue photoprotection than either violet or blue blocking IOLs. CONCLUSIONS: Action spectra for most retinal photosensitisers increase or peak in the violet part of the spectrum. Melanopsin, melatonin suppression, and rhodopsin sensitivities are all maximal in the blue part of the spectrum. Scotopic sensitivity and circadian photoentrainment decline with ageing. UV blocking IOLs provide older adults with the best possible rhodopsin and melanopsin sensitivity. Blue and violet blocking IOLs provide less photoprotection than middle aged crystalline lenses, which do not prevent age related macular degeneration (AMD). Thus, pseudophakes should wear sunglasses in bright environments if the unproved phototoxicity-AMD hypothesis is valid.
Inhibition of alpha(1-6)-linked fucose decreases inner retinal cells and increases photoreceptors in chicken retinal reaggregates.
We investigated the developmental role of alpha(1-6)-linked fucose, applying Aleuria aurantia lectin to a specific retinal regeneration system. Thereby, dissociated retinal cells of chicken embryos reaggregate, proliferate, and differentiate in vitro into histotypical spheres, so-called retinospheroids. Under the influence of A. aurantia lectin, processes of proliferation, differentiation and histogenesis of retinospheroids were disturbed. Extending these in vitro studies, we here show that A. aurantia lectin treatment decreases cells of the inner half retina and their processes into inner plexiform layer areas, as revealed by quantitative enzyme histochemistry for butyryl- and acetylcholinesterase, and immunohistochemistry using antibodies to acetylcholinesterase, Pax-6, calbindin-D, and F11. Concomitantly, the number of rod and red/green photoreceptors dramatically increases, using the antibodies rho4D2 and CERN901 (both specific for rods) and CERN906 (specific for red/green cones). These findings show that glycoproteins exhibiting fucose in alpha(1-6)-linkage are involved in processes determining retinal cell fate, strongly shifting the relative ratio of cells of the inner towards cells of the outer retina.
Assignment of panopsin (OPN3) to human chromosome band 1q43 by in situ hybridization and somatic cell hybrids.
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Genetics of color vision deficiencies.
The normal X-chromosome-linked color vision gene array is composed of a single red pigment gene followed by one or more green pigment genes. The high degree of homology between these genes predisposed them to unequal recombination, leading to gene deletions or the formation of red-green hybrid genes that explain the majority of the common red-green color vision deficiencies. Gene expression studies suggest that only the two most proximal genes of the array are expressed in the retina. The severity of the color vision defect is roughly related to the difference in absorption maxima of the photopigments encoded by the first two genes of the array. A single amino acid polymorphism (Ser180Ala) in the red pigment accounts for the subtle difference in normal color vision and influences the severity of color vision deficiency. Blue cone monochromacy is a rare disorder that involves absence of red and green cone function. It is caused either by deletion of a critical region that regulates expression of the red/green gene array, or by mutations that inactivate the red and green pigment genes. Total color blindness is another rare disease that involves complete absence of all cone function. A number of mutations in the genes encoding the cone-specific alpha- and beta-subunits of the cation channel and the alpha-subunit of transducin have been implicated in this disorder.
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.
Specific radioimmunoassay to investigate rod outer segment phagocytosis by retinal pigment epithelium in vitro.
A sensitive radioimmunoassay has been developed which allows rapid quantitation of rod outer segment (ROS) phagocytosis by retinal pigment epithelial (RPE) explants in vitro. It involves the use of an antiopsin antiserum, in conjunction with 125I-protein A as a second antibody, and utilizes permeabilization with ethanol to distinguish between the binding and ingestion phases of phagocytosis. This procedure will be used in the future to investigate potential regulatory factors of ROS phagocytosis by retinal pigment epithelium and to evaluate animal models of retinal degeneration.
Estimates of L:M cone ratio from ERG flicker photometry and genetics.
Estimates of L:M cone ratio for males with normal color vision were derived using the flicker-photometric electroretinogram (ERG). These were obtained by best fitting ERG spectral sensitivity functions to a weighted sum of long (L)- and middle (M)-wavelength-sensitive cone spectral absorption curves. Using the ERG, measurements can be made with extremely high precision, which leaves variation in the wavelength of maximal sensitivity (lambda(max)) of the cone photopigments as the major remaining source of inaccuracy in determining the ratio of cone contributions. Here that source of inaccuracy was largely eliminated through the use of individualized L-cone spectral absorption curves deduced from L-pigment gene sequences. The method was used on 62 normal males as part of an effort to obtain a true picture of how normal variations in L:M cone ratio are distributed. The percentage of L cones in the average eye was 65%L [where %L = 100 X L / (L+M)]. There were huge individual differences ranging from 28%-93%L, corresponding to more than a 30-fold range in L:M ratio (0.4-13). However, the most extreme values were relatively rare; 80% of the subjects fell within +/-15 %L of the mean, corresponding to a 4-fold range in L:M ratio (1-4). The method remedies major weaknesses inherent in earlier applications of flicker photometry to estimate cone ratio; however, it continues to depend on the assumption that the average L cone produces a response with an identical amplitude to that of the average M cone. A comparison of the ERG results with the distribution of cone ratios estimated from cone pigment messenger RNA in cadaver eyes indicates that the assumption generally holds true. However, there may be a small number of exceptions in which individuals have normally occurring (but relatively rare) amino acid substitutions in one of their pigments that significantly affect the physiology of the cone class containing that pigment, so as to reduce the amplitude of its contribution to the ERG. Consistent with this possibility, extreme cone contribution ratios were found to be associated with atypical L-pigment amino acid combinations.
Evaluating the human X-chromosome pigment gene promoter sequences as predictors of L:M cone ratio variation.
Men with normal color vision vary widely in the ratio of long- (L) to middle-wavelength sensitive (M) cones. This variation provides opportunities to test models for the mechanism that produces L versus M cones during development. The L and M photopigment genes lie in a tandem array. Each gene has a promoter, and upstream of each array there is a genetic element, termed the locus control region (LCR), that is required for the expression of both L and M pigment genes. During development, for each cell that has been determined to be an L or M cone, it has been proposed that the LCR acts as a stochastic selector which chooses one gene from the array to be expressed. In this model, the L and M promoters compete for contact with the LCR in each photoreceptor. Theoretically, the promoter that, by chance, is the first to successfully form a stable and permanent complex with the LCR commits the cell to a lifetime of exclusive expression of its associated gene. Under this model, it has been suggested that nucleotide differences in the promoters influence their ability to compete in forming a complex with the LCR. Thus, normal variation in L:M cone ratio is predicted to be associated with nucleotide polymorphisms in the promoters. Here we tested this hypothesis by comparing the L and M promoter sequences for 73 males with normal color vision for whom L:M cone ratio estimates had been obtained previously. The M gene promoter sequences were found to be identical for all 73 males and the L gene promoters were identical for 71 out of the 73 males. Two males had mutations where in each case the L promoter differed by one nucleotide substitution compared to normal. Both of the males with promoter mutations had unusual cone ratios which is consistent with the growing body of evidence indicating that the relative ability of the promoters to form a complex with the LCR is a factor in determining cone ratio. However, the vast majority of cone ratio differences were not associated with any difference in the promoter sequence. To explain the high degree of cone ratio variation among normal males, the mechanism that determines whether a cone is L or M must involve genetic elements that have a high degree of genetic polymorphism in the normal population. The results presented here indicate that there are additional genetic components of the mechanism which remain to be identified and incorporated into the present hypotheses.
Advantages and disadvantages of human dichromacy.
We compared the visual detection thresholds for cone-isolating stimuli of trichromats (those with normal color vision) with those of X-linked dichromats, who lack either the long-wavelength-sensitive (L) cones (protanopes) or middle-wavelength-sensitive (M) cones (deuteranopes). At low (1 Hz) temporal frequencies, dichromats have significantly higher (twofold) thresholds for all colored stimuli than trichromats; whereas at high (16 Hz) temporal frequencies, they perform as well or better than trichromats. The advantages of dichromats in detecting high temporally modulated targets can be related to an increased number, through replacement, of the remaining L- or M-cone type. However, their disadvantages in detecting low temporally modulated targets, even in directions of color space where their increased number of cone photoreceptors might be expected to be beneficial, are best explained in terms of the loss of L-M cone opponency and the inability of the visual pathways to reorganize to allow the detection of low-frequency luminance modulation.
An in vivo doxycycline-controlled expression system for functional studies of the retina.
PURPOSE: Transgenic mice were developed that express tetracycline-controlled transactivator 1 (tTA1) specifically in photoreceptor cells. In these mice the transcription of the gene of interest can be easily inactivated in the retina in a short time frame. METHODS: A construct was prepared containing tTA1 under control of the murine rhodopsin regulatory region. This construct was used for the generation of transgenic mice. In situ hybridization was performed to study the distribution of the transactivator in the retina. The activity of the transactivator was analyzed by mating the lines with a luciferase reporter transgenic mouse. tTA1 activity and doxycycline's ability to block it were analyzed by luciferase assay. The effects of tTA1 on the retina were assessed by histology and electrophysiology. RESULTS: Two transgenic lines were developed that specifically express tTA1 in photoreceptor cells. The time course of transgene expression replicated transcription of endogenous rhodopsin. tTA1 was not toxic to the retina. Transactivator activity was blocked readily by doxycycline. CONCLUSIONS: An expression system for photoreceptor cells was generated to drive transcription in a cell-specific and time-controllable manner. This system is suitable for the study of factors involved in retinal biology and of mutant forms of genes involved in retinal diseases.
Cell cycle regulation in retinal progenitors by glia-derived neurotrophic factor and docosahexaenoic acid.
PURPOSE: A recent study has shown that glia-derived neurotrophic factor (GDNF) and docosahexaenoic acid (DHA) promote the survival and differentiation of retina photoreceptors. The current study was undertaken to investigate whether these molecules participate in cell cycle regulation in retinal progenitors in vitro. METHODS: Developmental changes in the expression of the stem cell marker nestin and of cell cycle and differentiated neuron markers were analyzed in neuroblasts obtained from 1-day-old rat retinas. The effects of GDNF and DHA on those changes were then determined. RESULTS: Expression of nestin, found in more than one third of neuroblasts at day 1, rapidly decreased during development, with most neuroblasts acquiring the photoreceptor phenotype. GDNF increased the percentage of photoreceptor progenitors expressing nestin, whereas DHA reduced it, simultaneously enhancing photoreceptor differentiation. Several markers of cell cycle progression indicated that photoreceptor progenitors maintained an active cell cycle during the first 2 days in vitro. GDNF stimulated the cell cycle, increasing the number of dividing cells and generating more photoreceptor progenitors, whereas DHA induced cell cycle exit and photoreceptor differentiation. Analysis of the expression of the cyclin-Cdk inhibitor p27(Kip1) confirmed these results. CONCLUSIONS: GDNF and DHA acted as molecular cues, counterbalancing the decision of photoreceptors to remain in or exit the cell cycle. The results strongly suggest that both factors participate in determining the number of photoreceptors in vitro, regulating the cell cycle and survival at early and late stages of development, respectively. Hence, GDNF and DHA may coordinately control the histogenesis of photoreceptors in the retina by modulating both neurogenesis and apoptosis.
Functional and cellular responses in a novel rodent model of anterior ischemic optic neuropathy.
PURPOSE: Anterior ischemic optic neuropathy (AION) is caused by sudden loss of vascular supply to retinal ganglion cell (RGC) axons in the anterior portion of the optic nerve and is a major cause of optic nerve dysfunction. There has been no easily obtainable animal model of this disorder. The current study was conducted to design a novel model of rodent AION (rAION), to enable more detailed study of this disease. METHODS: A novel rodent photoembolic stroke model was developed that is directly analogous to human AION. Using histologic, electrophysiological, molecular- and cell biological methods, the early changes associated with isolated RGC axonal ischemia were characterized. RESULTS: Functional (electrophysiological) changes occurred in RGCs within 1 day after rAION, with a loss of visual evoked potential (VEP) amplitude that persisted in the long term. The retinal gene expression pattern rapidly changed after rAION induction, with an early (<1 day) initial induction of c-Fos mRNA, and loss of RGC-specific gene expression. RGC-specific protein expression declined 2 days after detectable mRNA level changes, and immunostaining suggested that multiple retinal layers react to isolated RGC axonal ischemia. CONCLUSIONS: rAION rapidly results in electrophysiological and histologic changes similar to clinical AION, with reactive responses in primary and supporting neuronal cell layers. The rAION model can enable a detailed analysis of the individual retinal and optic nerve changes that occur after optic nerve stroke, which may be useful in determining possible therapeutic interventions for this disorder.
Delayed regeneration of foveal cone photopigments in Vogt-Koyanagi-Harada disease at the convalescent stage.
PURPOSE: To evaluate the physiological characteristics of the macula in patients with Vogt-Koyanagi-Harada disease during the convalescent stage with specific reference to the kinetics of foveal cone photopigment regeneration. METHODS: Six eyes of three patients at the convalescent stage of Vogt-Koyanagi-Harada disease were studied. All the eyes had best corrected visual acuity of 1.0 or better and had had no recurrence of inflammation for at least 12 months after the last episode. Foveal cone densitometry (FCD), focal macular electroretinograms, color vision tests, two-color perimetry, and optical coherence tomography (OCT) were performed. RESULTS: No regeneration of cone photopigments was detected within the 7-minute testing time by FCD in all eyes at the first examination after the last episode. However, the other functional tests were normal, and the OCT-determined macular morphology was also normal. The regeneration kinetics of the foveal cone photopigment improved in three of six eyes at 36, 37, and 19 months after the last episode, whereas the other three remained delayed at 18, 18, and 49 months. CONCLUSIONS: These findings suggest that a disorder of the foveal cone photopigment regeneration, and its recovery, requires a significantly longer time than that of other macular functions in some patients with Vogt-Koyanagi-Harada disease.
Melanopsin is expressed in PACAP-containing retinal ganglion cells of the human retinohypothalamic tract.
PURPOSE: The putative circadian photoreceptor melanopsin is found in rodents in a subpopulation of intrinsic light-sensitive retinal ganglion cells (RGCs) constituting the retinohypothalamic tract (RHT). The study was conducted to determine whether melanopsin is expressed in the human retina and costored with the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP), a marker for the RHT, projecting to the suprachiasmatic nucleus (SCN). Furthermore, whether melanopsin expression is conserved in retinas of blind patients with severe retinal degeneration was investigated. METHODS: In situ hybridization and immunohistochemistry was used to demonstrate melanopsin synthesis in human eyes of 17 donors and two postmortem hypothalami containing the SCN. The coexistence of melanopsin and PACAP in elements of the retinohypothalamic tract was studied by dual-labeling immunocytochemistry. RESULTS: Melanopsin expression was found in a subpopulation of RGCs located in the ganglion cell layer and displaced in the inner nuclear cell layer. Melanopsin-containing cells comprised approximately 0. 8% of all RGCs, with a distinct morphology characterized by two to four dendritic processes constituting a panretinal network. Melanopsin immunoreactivity was primary present at perikaryal boundaries and neuronal processes and to some extent also in the cytoplasm. PACAP and melanopsin were colocalized in the RGCs and PACAP-containing nerve fibers, seemingly innervating the retinorecipient part of the SCN. Melanopsin-expressing RGCs were conserved in retinas of blind patients with severe degeneration of the outer and/or inner layers. CONCLUSIONS: Given the expression of melanopsin in PACAP-containing RGCs of the human RHT, this photoreceptor is a likely first base in the chain of events leading to photoentrainment of both normal and blind people.
Cyclic AMP prevents retraction of axon terminals in photoreceptors prepared for transplantation: an in vitro study.
PURPOSE: Cell transplantation has emerged as a possible remedy for degeneration and injury in the central nervous system (CNS). In the retina, photoreceptor transplantation is a potential treatment for retinal degenerative disease. Graft survival has been well documented, but evidence of functional recovery is lacking. A major obstacle to recovery of vision is lack of synapse formation between grafted photoreceptors and host bipolar and horizontal cells. A prior study demonstrated that photoreceptors prepared for transplantation undergo rapid morphologic changes, including retraction of axon terminals toward their cell bodies, away from potential synaptic partners, a phenomenon that may interfere with graft-host synaptic interaction after transplantation. In this study, prevention of retraction of photoreceptor axon terminals was possible by pharmacological intervention. METHODS: Photoreceptor sheets, prepared by vibratome sectioning, and full-thickness retinas, harvested from adult porcine eyes, were maintained in culture and treated with either the cyclic adenosine monophosphate analogue 8-(4-chlorophenylthio)-cyclic 3',5'-adenosine monophosphate (CPT-cAMP), or forskolin, an adenylyl cyclase stimulant, for up to 48 hours. RESULTS: Both CPT-cAMP and forskolin treatments successfully blocked retraction of photoreceptor axon terminals. This effect was not due to cell toxicity and was reversed after removal of treatment, indicating its specificity. CONCLUSIONS: Pharmacological manipulation of photoreceptor axonal plasticity may improve graft-host synaptic interaction after subretinal photoreceptor cell transplantation.