Author: Progress in Retinal and Eye Research

Evolution of Phototransduction, Vertebrate Photoreceptors and Retina

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Publication date: Available online 18 June 2013
Source:Progress in Retinal and Eye Research
Author(s): Trevor D. Lamb
Evidence is reviewed from a wide range of studies relevant to the evolution of vertebrate photoreceptors and phototransduction, in order to permit the synthesis of a scenario for the major steps that occurred during the evolution of cones, rods and the vertebrate retina. The ancestral opsin originated more than 700 Mya (million years ago) and duplicated to form three branches before cnidarians diverged from our own lineage. During chordate evolution, ciliary opsins (C-opsins) underwent multiple stages of improvement, giving rise to the ‘bleaching’ opsins that characterise cones and rods. Prior to the ‘2R’ rounds of whole genome duplication near the base of the vertebrate lineage, ‘cone’ photoreceptors already existed; they possessed a transduction cascade essentially the same as in modern cones, along with two classes of opsin: SWS and LWS (short- and long-wave-sensitive). These cones appear to have made synaptic contact directly onto ganglion cells, in a two-layered retina that resembled the pineal organ of extant non-mammalian vertebrates. Interestingly, those ganglion cells appear to be descendants of microvillar photoreceptor cells. No lens was associated with this two-layered retina, and it is likely to have mediated circadian timing rather than spatial vision. Subsequently, retinal bipolar cells evolved, as variants of ciliary photoreceptors, and greatly increased the computational power of the retina. With the advent of a lens and extraocular muscles, spatial imaging information became available for central processing, and gave rise to vision in vertebrates more than 500 Mya. The ‘2R’ genome duplications permitted the refinement of cascade components suitable for both rods and cones, and also led to the emergence of five visual opsins. The exact timing of the emergence of ‘true rods’ is not yet clear, but it may not have occurred until after the divergence of jawed and jawless vertebrates. [292 words]

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Amblyopia and binocular vision

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March 2013
Publication year: 2013
Source:Progress in Retinal and Eye Research, Volume 33

Amblyopia is the most common cause of monocular visual loss in children, affecting 1.3%–3.6% of children. Current treatments are effective in reducing the visual acuity deficit but many amblyopic individuals are left with residual visual acuity deficits, ocular motor abnormalities, deficient fine motor skills, and risk for recurrent amblyopia. Using a combination of psychophysical, electrophysiological, imaging, risk factor analysis, and fine motor skill assessment, the primary role of binocular dysfunction in the genesis of amblyopia and the constellation of visual and motor deficits that accompany the visual acuity deficit has been identified. These findings motivated us to evaluate a new, binocular approach to amblyopia treatment with the goals of reducing or eliminating residual and recurrent amblyopia and of improving the deficient ocular motor function and fine motor skills that accompany amblyopia.

Highlights

► There is now a substantial clinical trial evidence base for amblyopia treatment. ► Residual and recurrent amblyopia are common. ► We identified the central role of binocular vision in the genesis of amblyopia. ► New amblyopia treatments target the primary binocular dysfunction.

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Postnatal mammalian retinal development: Quantitative data and general rules

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November 2012
Publication year: 2012
Source:Progress in Retinal and Eye Research, Volume 31, Issue 6

This article is aimed at providing comparative quantitative data about postnatal mammalian retina development, and at searching for some general rules at both the descriptive and the mechanistic level. In mammals the eye continues to grow, and the retina continues to expand, much after the end of retinal cytogenesis. Thus, although the total number of retinal cells remains constant after cessation of mitotic activity (and the end of ‘physiological cell death’), the retinal surface area increases by a factor of two or more. In most mammals, ocular growth exceeds retinal expansion: the neural retina lines 70–80% of the inner ocular surface at the beginning but only about 40–60% in adults. Differential local expansion of the retina (the peripheral area increases more than the central one) can be explained by ‘passive stretching’ of the retinal tissue by the growing eyeball; it depends on the different biomechanical properties of the peripheral vs. central retinal tissue. The increasing retinal surface area allows for a re-distribution of cells such that the thickness of the (particularly, outer) nuclear layer(s) decreases proportional to the areal expansion. This causes a considerable developmental reduction of the number of cell nuclei ‘stacked above each other’ by a factor of more than two, and requires a translocation of the somata against their neighbors. We provide a physico-mathematical model of these oblique ‘down-sliding’ movements of the photoreceptor cell somata along the Müller cell process in the center of their columnar cell unit.

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Adaptation of the central retina for high acuity vision: Cones, the fovea and the avascular zone

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Available online 15 March 2013
Publication year: 2013
Source:Progress in Retinal and Eye Research

Presence of a fovea centralis is directly linked to molecular specification of an avascular area in central retina, before the fovea (or ‘pit’) begins to form. Modelling suggests that mechanical forces, generated within the eye, initiate formation of a pit within the avascular area, and its later remodelling in the postnatal period. Within the avascular area the retina is dominated by ‘midget’ circuitry, in which signals are transferred from a single cone to a single bipolar cell, then a single ganglion cell. Thus in inner, central retina there is relatively few lateral connections between neurons. This renders the region adaptable to tangential forces, that translocate of ganglion cells laterally/centrifugally, to form the fovea. Optical coherence tomography enables live imaging of the retina, and shows that there is greater variation in the morphology of foveae in humans than previously thought. This variation is associated with differences in size of the avascular area and appears to be genetically based, but can be modified by environmental factors, including prematurity. Even when the fovea is absent (foveal hypoplasia), cones in central retina adopt an elongated and narrow morphology, enabling them to pack more densely to increase the sampling rate, and to act as more effective waveguides. Given these findings, what then is the adaptive advantage of a fovea? We suggest that the advantages of having a pit in central retina are relatively few, and minor, but together work to enhance acuity.

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Ocular aldehyde dehydrogenases: Protection against ultraviolet damage and maintenance of transparency for vision

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March 2013
Publication year: 2013
Source:Progress in Retinal and Eye Research, Volume 33

Aldehyde dehydrogenase (ALDH) enzymes catalyze the NAD(P)+-dependent oxidation of a wide variety of endogenous and exogenous aldehydes to their corresponding acids. Some members of the ALDH superfamily of enzymes are abundantly expressed in the mammalian cornea and lens in a taxon-specific manner. Considered to be corneal and lens crystallins, they confer protective and transparent properties upon these ocular tissues. ALDH3A1 is highly expressed in the cornea of most mammals, with the exception of rabbit that expresses exclusively ALDH1A1 in the cornea. ALDH1A1 is present in both the cornea and lens of several animal species. As a result of their catalytic and non-catalytic functions, ALDH3A1 and ALDH1A1 proteins protect inner ocular tissues from ultraviolet radiation and reactive oxygen-induced damage. In addition, these corneal crystallins contribute to cellular transparency in corneal stromal keratocytes, supporting a structural role of these ALDH proteins. A putative regulatory function of ALDH3A1 on corneal cell proliferation has also been proposed. Finally, the three retinaldehyde dehydrogenases cooperatively mediate retinoic acid signaling during the eye development.

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Immunological homeostasis of the eye

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March 2013
Publication year: 2013
Source:Progress in Retinal and Eye Research, Volume 33

Uveitis is a sight-threatening disease caused by autoimmune or infection-related immune responses. Studies in experimental autoimmune uveitis and in human diseases imply that activated CD4+ T cells, Th1 and Th17 cells, play an effector role in ocular inflammation. The eye has a unique regional immune system to protect vision-related cells and tissues from these effector T cells. The immunological balance between the pathogenic CD4+ T cells and regional immune system in the eye contributes to the maintenance of ocular homeostasis and good vision. Current studies have demonstrated that ocular parenchymal cells at the inner surface of the blood-ocular barrier, i.e. corneal endothelial (CE) cells, iris pigment epithelial (PE) cells, ciliary body PE cells, and retinal PE cells, contribute to the regional immune system of the eye. Murine ocular resident cells directly suppress activation of bystander T cells and production of inflammatory cytokines. The ocular resident cells possess distinct properties of immunoregulation that are related to disparate anatomical location. CE cells and iris PE cells, which are located at the anterior segment of the eye and face the aqueous humor, suppress activation of T cells via cell-to-cell contact mechanisms, whereas retinal PE cells suppress the activation of T cells via soluble factors. In addition to direct immune suppression, the ocular resident cells have another unique immunosuppressive property, the induction of CD25+Foxp3+ Treg cells that also suppress the activation of bystander T cells. Iris PE cells convert CD8+ T cells into Treg cells, while retinal PE cells convert CD4+ T cells greatly and CD8+ T cells moderately into Treg cells. CE cells also convert both CD4+ T cells and CD8+ T cells into Treg cells. The immunomodulation by ocular resident cells is mediated by various soluble or membrane-bound molecules that include TGF-β TSP-1, B7-2 (CD86), CTLA-2α, PD-L1 (B7-H1), galectin 1, pigment epithelial-derived factor PEDF), GIRTL, and retinoic acid. Human retinal PE cells also possess similar immune properties to induce Treg cells. Although there are many issues to be answered, human Treg cells induced by ocular resident cells such as retinal PE cells and related immunosuppressive molecules can be applied as immune therapy for refractive autoimmune uveitis in humans in the future.

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Pax6: A multi-level regulator of ocular development

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September 2012
Publication year: 2012
Source:Progress in Retinal and Eye Research, Volume 31, Issue 5

Eye development has been a paradigm for the study of organogenesis, from the demonstration of lens induction through epithelial tissue morphogenesis, to neuronal specification and differentiation. The transcription factor Pax6 has been shown to play a key role in each of these processes. Pax6 is required for initiation of developmental pathways, patterning of epithelial tissues, activation of tissue-specific genes and interaction with other regulatory pathways. Herein we examine the data accumulated over the last few decades from extensive analyses of biochemical modules and genetic manipulation of the Pax6 gene. Specifically, we describe the regulation of Pax6’s expression pattern, the protein’s DNA-binding properties, and its specific roles and mechanisms of action at all stages of lens and retinal development. Pax6 functions at multiple levels to integrate extracellular information and execute cell-intrinsic differentiation programs that culminate in the specification and differentiation of a distinct ocular lineage.

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Optical superresolution and visual hyperacuity

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September 2012
Publication year: 2012
Source:Progress in Retinal and Eye Research, Volume 31, Issue 5

Classically, diffraction theory sets a boundary for the resolving capacity of optical instruments. Yet some visual thresholds have values much better than the traditional resolution limit. Recent developments in superresolution, an area of optical physics and engineering with claims of transcending the stated resolution limits of optical instruments, are reviewed and their possible relevance to visual spatial processing and to the exploration of the eye’s structure are assessed. In optical or diffractive superresolution the transmitted spatial-frequency band is not so much extended as either multiplexed with or displaced into regions that are usually beyond reach, with no overall gain in information transfer because prior knowledge is used to make inferences of possible object structure from the image. The Uncertainty Principle for photon position and momentum is never disobeyed. The study of the neural substrate of visual hyperacuity does, however, overlap that of “geometrical superresolution,” in which techniques are used for transcending limits imposed by the receptor lattice in analyzing fine image structure.

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X-linked juvenile retinoschisis: Clinical diagnosis, genetic analysis, and molecular mechanisms

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May 2012
Publication year: 2012
Source:Progress in Retinal and Eye Research, Volume 31, Issue 3

X-linked juvenile retinoschisis (XLRS, MIM 312700) is a common early onset macular degeneration in males characterized by mild to severe loss in visual acuity, splitting of retinal layers, and a reduction in the b-wave of the electroretinogram (ERG). The RS1 gene (MIM 300839) associated with the disease encodes retinoschisin, a 224 amino acid protein containing a discoidin domain as the major structural unit, an N-terminal cleavable signal sequence, and regions responsible for subunit oligomerization. Retinoschisin is secreted from retinal cells as a disulphide-linked homo-octameric complex which binds to the surface of photoreceptors and bipolar cells to help maintain the integrity of the retina. Over 190 disease-causing mutations in the RS1 gene are known with most mutations occurring as non-synonymous changes in the discoidin domain. Cell expression studies have shown that disease-associated missense mutations in the discoidin domain cause severe protein misfolding and retention in the endoplasmic reticulum, mutations in the signal sequence result in aberrant protein synthesis, and mutations in regions flanking the discoidin domain cause defective disulphide-linked subunit assembly, all of which produce a non-functional protein. Knockout mice deficient in retinoschisin have been generated and shown to display most of the characteristic features found in XLRS patients. Recombinant adeno-associated virus (rAAV) mediated delivery of the normal RS1 gene to the retina of young knockout mice result in long-term retinoschisin expression and rescue of retinal structure and function providing a ‘proof of concept’ that gene therapy may be an effective treatment for XLRS.

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