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The Journal of Physiology Oct 2016One hundred and fifty years ago Max Schultze first proposed the duplex theory of vision, that vertebrate eyes have two types of photoreceptor cells with differing... (Review)
Review
One hundred and fifty years ago Max Schultze first proposed the duplex theory of vision, that vertebrate eyes have two types of photoreceptor cells with differing sensitivity: rods for dim light and cones for bright light and colour detection. We now know that this division is fundamental not only to the photoreceptors themselves but to the whole of retinal and visual processing. But why are rods more sensitive, and how did the duplex retina first evolve? Cells resembling cones are very old, first appearing among cnidarians; the emergence of rods was a key step in the evolution of the vertebrate eye. Many transduction proteins have different isoforms in rods and cones, and others are expressed at different levels. Moreover rods and cones have a different anatomy, with only rods containing membranous discs enclosed by the plasma membrane. These differences must be responsible for the difference in absolute sensitivity, but which are essential? Recent research particularly expressing cone proteins in rods or changing the level of expression seem to show that many of the molecular differences in the activation and decay of the response may have each made a small contribution as evolution proceeded stepwise with incremental increases in sensitivity. Rod outer-segment discs were not essential and developed after single-photon detection. These experiments collectively provide a new understanding of the two kinds of photoreceptors and help to explain how gene duplication and the formation of rod-specific proteins produced the duplex retina, which has remained remarkably constant in physiology from amphibians to man.
Topics: Animals; Protein Isoforms; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Vision, Ocular
PubMed: 27218707
DOI: 10.1113/JP272556 -
Progress in Retinal and Eye Research Nov 2017Age related macular degeneration (AMD) is a complex multifactorial disease caused by the interplay of age and genetic and environmental risk factors. A common feature... (Review)
Review
Age related macular degeneration (AMD) is a complex multifactorial disease caused by the interplay of age and genetic and environmental risk factors. A common feature observed in early and both forms of late AMD is the breakdown of the physiologically immunosuppressive subretinal environment and the protracted accumulation of mononuclear phagocytes (MP). We here discuss the origin and nature of subretinal MPs, the mechanisms that lead to their accumulation, the inflammatory mediators they produce as well as the consequences of their chronic presence on photoreceptors, retinal pigment epithelium and choroid. Recent advances highlight how both genetic and environmental risk factors directly promote subretinal inflammation and tip the balance from a beneficial inflammation that helps control debris accumulation to detrimental chronic inflammation and destructive late AMD. Finally, we discuss how changes in life style or pharmacological intervention can help to break the vicious cycle of inflammation and degeneration, restore the immunosuppressive properties of the subretinal space, and reestablish homeostasis.
Topics: Choroid; Humans; Life Style; Macular Degeneration; Macular Edema; Phagocytes; Photoreceptor Cells; Retinal Pigment Epithelium
PubMed: 28602950
DOI: 10.1016/j.preteyeres.2017.06.002 -
Progress in Retinal and Eye Research Sep 2022In the vertebrate retina, rods and cones both detect light, but they differ in functional aspects such as light sensitivity and temporal resolution, and in some cell... (Review)
Review
In the vertebrate retina, rods and cones both detect light, but they differ in functional aspects such as light sensitivity and temporal resolution, and in some cell biological aspects. For functional aspects, both types of photoreceptors use a phototransduction cascade, consisting of a series of enzymatic reactions, to convert photon capture to an electrical signal. To understand the mechanisms underlying the functional differences between rods and cones at the molecular level, we compared biochemically, each of the reactions in the phototransduction cascades of rods and cones using the cells isolated and purified from carp retina. Although the cascade proteins are identical or are functionally similar between rods and cones, their activities together with their expression levels are mostly different. In general, reactions that generate a response are somewhat less effective in cones than in rods, but each of the reactions for termination and recovery of a response are much more effective in cones. These findings explain lower light sensitivity and briefer light responses in cones than in rods. In addition, our considerations suggest that a Ca-binding protein, S-modulin or recoverin, has a currently unnoticed role in shaping light responses. Upon comparison of the expression levels of proteins and/or mRNAs using purified cells, several proteins were found to be specifically or predominantly expressed in cones. These proteins will be of interest in future studies aimed at characterizing the differences between rods and cones.
Topics: Animals; Humans; Light Signal Transduction; Photophobia; Retina; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells
PubMed: 34974196
DOI: 10.1016/j.preteyeres.2021.101040 -
Experimental Eye Research Oct 2020Inherited retinal degenerative disorders such as retinitis pigmentosa and Usher syndrome are characterized by progressive death of photoreceptor cells. To restore vision...
Inherited retinal degenerative disorders such as retinitis pigmentosa and Usher syndrome are characterized by progressive death of photoreceptor cells. To restore vision to patients blinded by these diseases, a stem cell-based photoreceptor cell replacement strategy will likely be required. Although retinal stem cell differentiation protocols suitable for generating photoreceptor cells exist, they often yield a rather heterogenous mixture of cell types. To enrich the donor cell population for one or a few cell types, scientists have traditionally relied upon the use of antibody-based selection approaches. However, these strategies are quite labor intensive and require animal derived reagents and equipment that are not well suited to current good manufacturing practices (cGMP). The purpose of this study was to develop and evaluate a microfluidic cell sorting device capable of exploiting the physical and mechanical differences between retinal cell types to enrich specific donor cell populations such as Retinal Pigment Epithelial (RPE) cells and photoreceptor cells. Using this device, we were able to separate a mixture of RPE and iPSC-derived photoreceptor precursor cell lines into two substantially enriched fractions. The enrichment factor of the RPE fraction was 2 and that of the photoreceptor precursor cell fraction was 2.7. Similarly, when human retina, obtained from 3 independent donors, was dissociated and passed through the sorting device, the heterogeneous mixture could be reliably sorted into RPE and photoreceptor cell rich fractions. In summary, microfluidic cell sorting is a promising approach for antibody free enrichment of retinal cell populations.
Topics: Animals; Cell Differentiation; Cell Line; Humans; Microfluidics; Microscopy, Atomic Force; Photoreceptor Cells; Retinal Degeneration; Retinal Pigment Epithelium
PubMed: 32771499
DOI: 10.1016/j.exer.2020.108166 -
Progress in Retinal and Eye Research Jul 2019Photoreceptors are polarized neurons, with very specific subcellular compartmentalization and unique requirements for protein expression and trafficking. Each... (Review)
Review
Photoreceptors are polarized neurons, with very specific subcellular compartmentalization and unique requirements for protein expression and trafficking. Each photoreceptor contains an outer segment, the site of photon capture that initiates vision, an inner segment that houses the biosynthetic machinery and a synaptic terminal for signal transmission to downstream neurons. Outer segments and inner segments are connected by a connecting cilium (CC), the equivalent of a transition zone (TZ) of primary cilia. The connecting cilium is part of the basal body/axoneme backbone that stabilizes the outer segment. This report will update the reader on late developments in photoreceptor ciliogenesis and transition zone formation, specifically in mouse photoreceptors, focusing on early events in photoreceptor ciliogenesis. The connecting cilium, an elongated and narrow structure through which all outer segment proteins and membrane components must traffic, functions as a gate that controls access to the outer segment. Here we will review genes and their protein products essential for basal body maturation and for CC/TZ genesis, sorted by phenotype. Emphasis is given to naturally occurring mouse mutants and gene knockouts that interfere with CC/TZ formation and ciliogenesis.
Topics: Animals; Basal Bodies; Cilia; Membrane Proteins; Models, Animal; Photoreceptor Cells; Protein Transport; Signal Transduction
PubMed: 30590118
DOI: 10.1016/j.preteyeres.2018.12.004 -
Experimental Eye Research Apr 2015The interphotoreceptor matrix (IPM) is a highly organized structure with interconnected domains surrounding cone and rod photoreceptor cells and extends throughout the... (Review)
Review
The interphotoreceptor matrix (IPM) is a highly organized structure with interconnected domains surrounding cone and rod photoreceptor cells and extends throughout the subretinal space. Based on known roles of the extracellular matrix in other tissues, the IPM is thought to have several prominent functions including serving as a receptor for growth factors, regulating retinoid transport, participating in cytoskeletal organization in surrounding cells, and regulation of oxygen and nutrient transport. In addition, a number of studies suggest that the IPM also may play a significant role in the etiology of retinal degenerative disorders. In this review, we describe the present knowledge concerning the structure and function of the IPM under physiological and pathological conditions.
Topics: Extracellular Matrix; Humans; Photomicrography; Photoreceptor Cells, Vertebrate
PubMed: 25819450
DOI: 10.1016/j.exer.2015.02.017 -
Annual Review of Vision Science Sep 2020Photoreceptors are highly specialized sensory neurons with unique metabolic and physiological requirements. These requirements are partially met by Müller glia and... (Review)
Review
Photoreceptors are highly specialized sensory neurons with unique metabolic and physiological requirements. These requirements are partially met by Müller glia and cells of the retinal pigment epithelium (RPE), which provide essential metabolites, phagocytose waste, and control the composition of the surrounding microenvironment. A third vital supporting cell type, the retinal microglia, can provide photoreceptors with neurotrophic support or exacerbate neuroinflammation and hasten neuronal cell death. Understanding the physiological requirements for photoreceptor homeostasis and the factors that drive microglia to best promote photoreceptor survival has important implications for the treatment and prevention of blinding degenerative diseases like retinitis pigmentosa and age-related macular degeneration.
Topics: Animals; Apoptosis; Ependymoglial Cells; Humans; Macrophage Activation; Phagocytosis; Photoreceptor Cells; Retinal Cone Photoreceptor Cells; Retinal Degeneration; Retinal Pigment Epithelium; Signal Transduction
PubMed: 32936734
DOI: 10.1146/annurev-vision-121219-081730 -
Biochemical Pharmacology Sep 2022Pathological deterioration of mitochondrial function is increasingly linked with multiple degenerative illnesses as a mediator of a wide range of neurologic and... (Review)
Review
Pathological deterioration of mitochondrial function is increasingly linked with multiple degenerative illnesses as a mediator of a wide range of neurologic and age-related chronic diseases, including those of genetic origin. Several of these diseases are rare, typically defined in the United States as an illness affecting fewer than 200,000 people in the U.S. population, or about one in 1600 individuals. Vision impairment due to mitochondrial dysfunction in the eye is a prominent feature evident in numerous primary mitochondrial diseases and is common to the pathophysiology of many of the familiar ophthalmic disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma and retinopathy of prematurity - a collection of syndromes, diseases and disorders with significant unmet medical needs. Focusing on metabolic mitochondrial pathway mechanisms, including the possible roles of cuproptosis and ferroptosis in retinal mitochondrial dysfunction, we shed light on the potential of α-lipoyl-L-carnitine in treating eye diseases. α-Lipoyl-L-carnitine is a bioavailable mitochondria-targeting lipoic acid prodrug that has shown potential in protecting against retinal degeneration and photoreceptor cell loss in ophthalmic indications.
Topics: Carnitine; Humans; Infant, Newborn; Mitochondria; Photoreceptor Cells; Retina; Retinal Degeneration
PubMed: 35835206
DOI: 10.1016/j.bcp.2022.115168 -
Pflugers Archiv : European Journal of... Sep 2021Rod and cone photoreceptors of the vertebrate retina utilize cGMP as the primary intracellular messenger for the visual signaling pathway that converts a light stimulus... (Review)
Review
Rod and cone photoreceptors of the vertebrate retina utilize cGMP as the primary intracellular messenger for the visual signaling pathway that converts a light stimulus into an electrical response. cGMP metabolism in the signal-transducing photoreceptor outer segment reflects the balance of cGMP synthesis (catalyzed by guanylyl cyclase) and degradation (catalyzed by the photoreceptor phosphodiesterase, PDE6). Upon light stimulation, rapid activation of PDE6 by the heterotrimeric G-protein (transducin) triggers a dramatic drop in cGMP levels that lead to cell hyperpolarization. Following cessation of the light stimulus, the lifetime of activated PDE6 is also precisely regulated by additional processes. This review summarizes recent advances in the structural characterization of the rod and cone PDE6 catalytic and regulatory subunits in the context of previous biochemical studies of the enzymological properties and allosteric regulation of PDE6. Emphasis is given to recent advances in understanding the structural and conformational changes underlying the mechanism by which the activated transducin α-subunit binds to-and relieves inhibition of-PDE6 catalysis that is controlled by its intrinsically disordered, inhibitory γ-subunit. The role of the regulator of G-protein signaling 9-1 (RGS9-1) in regulating the lifetime of the transducin-PDE6 is also briefly covered. The therapeutic potential of pharmacological compounds acting as inhibitors or activators targeting PDE6 is discussed in the context of inherited retinal diseases resulting from mutations in rod and cone PDE6 genes as well as other inherited defects that arise from excessive cGMP accumulation in retinal photoreceptor cells.
Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 6; Humans; Protein Structure, Secondary; Protein Structure, Tertiary; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Vision, Ocular
PubMed: 33860373
DOI: 10.1007/s00424-021-02562-x -
Cell Death & Disease Dec 2023Photoreceptor cell death and immune cell infiltration are two major events that contribute to retinal degeneration. However, the relationship between these two events...
Photoreceptor cell death and immune cell infiltration are two major events that contribute to retinal degeneration. However, the relationship between these two events has not been well delineated, primarily because of an inadequate understanding of the immunological processes involved in photoreceptor degeneration, especially that of peripheral leukocytes that infiltrate the subretinal space and retinal tissues. In this work, we characterized the role of leukocyte infiltration within the detached retina. We observed that CD45 CD11b Ly6G neutrophils and CD45 CD11b Ly6G Ly6C monocytes are the predominant peripheral immune cell populations that infiltrate the retinal and subretinal space after detachment. Selective depletion of monocytes or neutrophils using cell-specific targeting is neuroprotective for photoreceptors. These results indicate that peripheral innate immune cells contribute to photoreceptor degeneration, and targeting these immune cell populations could be therapeutic during retinal detachment.
Topics: Humans; Animals; Retinal Detachment; Monocytes; Neutrophils; Photoreceptor Cells; Retina; Retinal Degeneration; Photoreceptor Cells, Vertebrate; Disease Models, Animal
PubMed: 38102109
DOI: 10.1038/s41419-023-06350-6