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store.elsevier.com CONTRIBUTORS Zsolt Ablonczy Department of Ophthalmology, Albert Florens Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA Leopold Adler IV Department of Ophthalmology, Albert Florens Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA S Amer Riazuddin Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Jeffrey H Boatright Department of Ophthalmology, Emory University School of Medicine, Atlanta, and Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, Georgia, USA Hannah E Bowrey Department of Ophthalmology, Albert Florens Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA Nicholas P Boyer Department of Ophthalmology, Albert Florens Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA Barbara M Braunger Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany Ranjay Chakraborty Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, USA Chunhe Chen Department of Ophthalmology, Albert Florens Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA Seung-il Choi Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea Micah A Chrenek Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, USA Rosalie K Crouch Department of Ophthalmology, Albert Florens Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA xv xvi Contributors Ales Cvekl Departments of Genetics and Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, New York, USA Lucian V Del Priore Department of Ophthalmology, Albert Florens Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA Allen O Eghrari Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA J Fielding Hejtmancik Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA Mark A Fields Department of Ophthalmology, Albert Florens Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA Rudolf Fuchshofer Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany James L Funderburgh Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Eldon E Geisert Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, USA Jie Gong Department of Ophthalmology, Albert Florens Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA John D Gottsch Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Hans E Grossniklaus Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, USA Andrew J Hertsenberg Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Shengping Hou The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Lab of Ophthalmology, Chongqing Eye Institute, Chongqing, PR China Winston Whei-Yang Kao Edith Crawley Ophthalmic Research Laboratory, Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA Aize Kijlstra University Eye Clinic Maastricht, Maastricht, The Netherlands Contributors xvii Eung Kweon Kim Department of Ophthalmology, Vision Research Institute, Severance Hospital; Corneal Dystrophy Research Institute, and BK21 Plus Project for Medical Science and Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea Masahiro Kono Department of Ophthalmology, Albert Florens Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA Yiannis Koutalos Department of Ophthalmology, Albert Florens Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA Hun Lee Department of Ophthalmology, Vision Research Institute, Severance Hospital, and Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea Chia-Yang Liu Edith Crawley Ophthalmic Research Laboratory, Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA Wei Liu Departments of Genetics and Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, New York, USA Peter Y Lwigale Department of Biosciences, Rice University, Houston, Texas, USA Caitlin E Mac Nair Ophthalmology and Visual Sciences, and Cellular and Molecular Pathology Graduate Program, University of Wisconsin—Madison, Madison, Wisconsin, USA Rebecca McGreal Departments of Genetics and Ophthalmology and Visual Sciences, Albert Einstein College of Medicine, Bronx, New York, USA Pia R Mendoza Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, USA Ravi Metlapally UC Berkeley School of Optometry, Berkeley, California, USA T Michael Redmond Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, NIH, Bethesda, Maryland, USA Robert S Molday Department of Biochemistry and Molecular Biology, Centre for Macular Research, University of British Columbia, Vancouver, British Columbia, Canada Robert W Nickells Ophthalmology and Visual Sciences, University of Wisconsin—Madison, Madison, Wisconsin, USA xviii Contributors John M Nickerson Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, USA Machelle T Pardue Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, USA Kevin Schey Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, USA Robin H Schmidt Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, USA Daniel Schorderet IRO - Institute for Research in Ophthalmology, Sion; Faculty of Life Sciences, Swiss Federal Institute of Technology, and Department of Ophthalmology, University of Lausanne, Lausanne, Switzerland Alan Shiels Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, Missouri, USA Deborah L Stenkamp Department of Biological Sciences, University of Idaho, Moscow, Idaho, USA Felix L Struebing Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, USA Ernst R Tamm Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany Janey L Wiggs Harvard Medical School, and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA Christine F Wildsoet School of Optometry, University of California, Berkeley, California, USA Charles B Wright Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, USA Peizeng Yang The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Lab of Ophthalmology, Chongqing Eye Institute, Chongqing, PR China Qingjiong Zhang State Key Lab of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, PR China Yan Zhang School of Optometry, University of California, Berkeley, California, USA PREFACE The only thing worse than being blind is having sight but no vision Helen Keller The visual process is complex, depending on a combination of precise functions of the anterior segment, which serve to focus light precisely on the retina, and the posterior segment, which receives light signals, transforms them into electrical signals, and performs preliminary processing before transmitting them through the optic nerve and pathways to the visual cortex Each component of this system must function precisely and dependably for correct vision This requires that each part of the visual system undergoes appropriate developmental regulation, that each molecule in the various metabolic and functional pathways functions correctly, and that they all interact seamlessly in carrying out visual perception Finally, the biological systems that support and maintain homeostasis of the cells making up the visual system are required to protect and preserve vision over the lifetime of the individual to prevent age-related causes of blindness such as age-related cataract and macular degeneration One way in which to gain insight into the intricate processes supporting vision is through the examination of inherited diseases affecting vision, and from these the proteins and pathways which they affect In addition to obvious candidates, such as rhodopsin for retinal degenerations and lens crystallins for cataracts, the study of inherited visual diseases has identified previously unsuspected pathways and processes critical for visual function, including the role of complement and other immune regulators in the retina and processes such as message sequestration and autophagy in the lens However, the process works both ways: in order to study or even understand the molecular genetics of vision, one must have a firm foundation in the basic biochemistry, cell and developmental biology, and molecular biology of its component parts It is this interrelationship between the basic sciences and the study of inherited diseases, and eventually the clinical application of knowledge derived from both, that this book aspires to delineate In order to accomplish this intertwining of basic biology, genetics, and clinical application, coverage of each component of the eye begins with its developmental biology and progresses through its biochemistry and molecular biology before finishing with the molecular genetics of its inherited diseases The material aims at being approachable by a graduate student xix xx Preface or even an advanced undergraduate, while at the same time being of sufficient depth to provide even an advanced researcher a concise overview of each area In that vein, while avoiding being cumbersome each chapter is sufficiently referenced to provide access to the original literature in the area which it covers Finally, the chapters are written to maintain the interest of the reader and hopefully will inspire young scientists to pursue a career in vision research J FIELDING HEJTMANCIK JOHN M NICKERSON CHAPTER ONE Overview of the Visual System J Fielding Hejtmancik*, John M Nickerson†,1 *Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA † Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, USA Corresponding author: e-mail address: litjn@emory.edu Abstract This introduction provides an overview of the retina, in which we survey the fundus, layers of the retina, retinal cell types, visual transduction cascade, vitamin A cycle, neuronal wiring of the retina, and blood supply of the retina The visual system includes the optical components of the anterior segment of the eye: in order, the cornea, the aqueous humor, and the lens; and the posterior segment, including the vitreous body, the retina, and the optic nerve Finally, the visual system includes the optic tracts and optic radiations, transmitting neural signals to the visual cortex, and several additional nuclei of the brain (Fig 1) Each of these components is critical in receiving, transmitting, and interpreting visual information The optical components in the anterior segment of the eye focus light onto the retina, which then transduces the light signal into neural signals In addition, the retina also carries out initial processing of the neural signals before passing them through the optic nerves and tracts to central nervous system components that carry out their elaborate processing and integration with other senses In addition, the oculomotor system, basically the efferent arm of the visual system, controls stability of position of the eyes as well as directing and coordinating movements of the eyes to objects of interest Light initially traverses the anterior chamber where it first passes through the transparent cornea, aqueous humor, lens, and vitreous body (Fig 1) The speed with which light travels through each of these components is inversely proportional to its density, with the ratio of the velocity of light in a vacuum to the velocity in medium being the refractive index Thus, light waves striking the surface of the cornea at an angle are slowed differentially, so that the light entering the cornea first is slowed more than that which travels longer through air This bends the direction of the light called refraction If the components of the anterior segment, especially the cornea and lens, develop Progress in Molecular Biology and Translational Science, Volume 134 ISSN 1877-1173 http://dx.doi.org/10.1016/bs.pmbts.2015.05.006 # 2015 Elsevier Inc All rights reserved J Fielding Hejtmancik and John M Nickerson Figure Overview of the eye including the anterior and posterior segments The refraction of light rays from the fixation point at the tip of the arrow to the focal point on the retina represents the summed effects of the anterior and posterior surfaces of the cornea and lens The image of the arrow is projected in an inverted orientation on the retina into the proper shape and optical density, and are appropriately transparent, light rays originating from point source similarly are focused onto a single point on the retina This results in the image of an object being projected in an inverted fashion onto the retina, so that the inferior visual field is projected onto the superior region of the retina, and the nasal visual fields are projected onto the temporal retina The entire biology of the anterior segment is oriented toward accomplishing the clear transmission and sharp focusing of light onto the retina, and many of the genetic lesions of this part of the eye interfere with this task In the retina, the light signals transmitted by the anterior segment are converted to neural signals that undergo some initial processing before being transmitted through the optic nerve and radiations to the brain The retina comprises two functional and structural parts: the retinal pigment epithelium or RPE, which is the nonneural component, and the adjacent but distinct neural or sensory retina RPE cells contain melanin granules, which absorb light passed through the retina, preventing its reflection by the sclera, which would and degrade the quality of vision In addition, the cells of the RPE aid the photoreceptors by recycling visual pigments and phagocytizing shed photoreceptor outer-segment tips This requires that the outer segments including the visual pigments are physically close to the RPE layer Overview of the Visual System Conversely, the neural processing networks of the retina are the anteriormost structures, through which light passes before stimulating the photoreceptor cells in the posterior layer of the retina adjacent to the RPE (Fig 2) The neural retina is composed of six neuronal-cell types as well as nonneuronal glial Muăller cells These exist in three nuclear layers: from anterior to posterior the ganglion cell, inner nuclear, and outer nuclear layers, separated by the inner plexiform and outer plexiform layers, in which synapses occur The photoreceptor cells, whose cell bodies lie in the outer nuclear layer and whose outer segments lie adjacent to the RPE, carry out phototransduction, the biochemical process of transforming light to the electrical energy of neural signals There are two types of these highly specialized cells: rod and cone cells Rods contain rhodopsin and occur at greater density in the peripheral retina They mediate black and white vision and are able to detect light under dim illumination, important for night vision Cones are densely packed in the central retina, especially the macula, and carry out precision and color vision under strong illumination, for example in daylight The photoreceptor cells synapse with horizontal and bipolar cells in the outer plexiform layer Bipolar cells correspondingly synapse with amacrine and ganglion cells in the inner plexiform layer The cell bodies of the amacrine, bipolar, and horizontal, as well as interplexiform cells lie in the inner nuclear layer, while the cell bodies of the ganglion cells lie in the ganglion cell layer Finally, axons of the ganglion cells traverse the nerve fiber Figure The vertebrate retina Schematic of the cells in the retina ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer; R, rod cell; C, cone cell; B, bipolar cell; H, horizontal cell; A, amacrine cell; G, ganglion cell; RPE, retinal pigmented epithelium e8 Leopold Adler IV et al Figure Rod photoreceptor outer segments reduce all-trans but not 11-cis retinal (A) Scheme describing the fate of all-trans and 11-cis retinal added to intact darkadapted rod photoreceptors All-trans retinal is reduced by RDH8 to all-trans retinol and hence may not form lipofuscin precursors 11-cis retinal, being a poor substrate, is not reduced by RDH8; in addition, the cells being dark-adapted, there is no opsin for 11-cis retinal to combine with So, 11-cis retinal is available to form lipofuscin precursors (B) Outer segment fluorescence (excitation 490 nm; emission >515 nm) of wild-type dark-adapted metabolically intact rod photoreceptors after exposure to μM all-trans or 11-cis retinal for Numbers of cells are shown within each column Data replotted from Figure of Boyer et al.33 The asymmetric ability of rod outer segments to process the two retinal isomers makes concrete physiological sense All-trans retinal is a by-product of the detection of light that can be rapidly eliminated On the other hand, the rapid elimination of 11-cis retinal would prevent the regeneration of rhodopsin and interfere with the ability of the cell to detect light Nevertheless, rod photoreceptors have mechanisms to prevent the excessive accumulation of 11-cis retinal In rod outer segments, in a reaction mediated by phosphatidylethanolamine, excess 11-cis retinal is slowly isomerized to all-trans, which can then be eliminated by RDH8.42 In rod inner segments, any excess 11-cis retinal that could leak from the outer segment would be reduced by RDH12, which has no isomeric specificity.46,52 LIPOFUSCIN AND RHODOPSIN REGENERATION The origins of lipofuscin in the reactions of 11-cis and all-trans retinal with rod outer segments are representative of its close relation with the pathways that underlie the ability of the retina to detect light (Fig 5) The process of light detection begins with the absorption of light by the visual pigment rhodopsin present in rod outer segments Absorption of a photon isomerizes the rhodopsin chromophore from 11-cis to all-trans generating an active rhodopsin intermediate, which initiates the reactions culminating in a change in 11-cis Retinal Origins of Lipofuscin e9 Figure Lipofuscin precursors form in photoreceptor outer segments as a side product of the reactions that regenerate rhodopsin Lipofuscin precursors can form from either all-trans or 11-cis retinal All-trans retinal is released by photoactivated rhodopsin following light excitation, and reduced by RDH8 to all-trans retinol, which can be recycled to reform 11-cis retinal 11-cis retinal enters the outer segment and combines with opsin to regenerate rhodopsin Abbreviations: RPE, retinal pigment epithelium; OS, outer segments; IS: inner segments; ONL, outer nuclear layer, OPL, outer plexiform layer; Rh, rhodopsin; MRh, metarhodopsin II the photoreceptor membrane potential and converting the absorption of the photon to an electrical signal.36 Light absorption however destroys rhodopsin by isomerizing its chromophore from 11-cis to all-trans For vision to be possible, the regeneration of rhodopsin is necessary and requires two steps: one, the removal of the all-trans chromophore, and two, the supply of fresh 11-cis retinal Removal of the all-trans chromophore is achieved through the release of all-trans retinal by photoactivated rhodopsin, leaving behind opsin Fresh 11-cis retinal is supplied by the RPE to the rod outer segment, where it combines with opsin to regenerate rhodopsin.37–39 Both 11-cis and all-trans retinal are thus necessary intermediates of the rhodopsin regeneration process, an essential aspect of the light-detecting ability of the photoreceptor cells Because of the close link between lipofuscin generation and physiological function, attempts to address the problem of lipofuscin toxicity by limiting its generation face a difficult challenge: inhibiting the generation of 11-cis and all-trans retinal in order to reduce the levels of lipofuscin would interfere with the light-detecting ability of the retina The point is plainly made by the Rpe65À/À mice, which, by virtue of their inability to generate 11-cis retinal, have greatly suppressed levels of lipofuscin, but at the same time are essentially blind An important research direction therefore would be to find means to reduce lipofuscin e10 Leopold Adler IV et al levels without interfering with the process of light detection It is critical to point out that many of the conclusions presented in this chapter regarding the origins of lipofuscin and the relative contributions of 11-cis and all-trans retinal are based mainly on experimental results from mice It is vital to examine the process in other species, especially in those that have a macula The significance of such studies is underscored by the striking incongruence between the distributions of lipofuscin and A2E found in the human RPE.53 ACKNOWLEDGMENTS Supported by NIH/NEI Grants EY014850, EY019065, and an unrestricted grant to the Storm Eye Institute by Research to Prevent Blindness, Inc 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Reduction of all-trans-retinal in vertebrate rod photoreceptors requires the combined action of RDH8 and RDH12 J Biol Chem 2012;287:24662–24670 47 Maeda A, Maeda T, Imanishi Y, et al Role of photoreceptor-specific retinol dehydrogenase in the retinoid cycle in vivo J Biol Chem 2005;280:18822–18832 48 Rattner A, Smallwood PM, Nathans J Identification and characterization of all-transretinol dehydrogenase from photoreceptor outer segments, the visual cycle enzyme that reduces all-trans-retinal to all-trans-retinol J Biol Chem 2000;275:11034–11043 49 Futterman S, Hendrickson A, Bishop PE, et al Metabolism of glucose and reduction of retinaldehyde in retinal photoreceptors J Neurochem 1970;17:149–156 50 Adler IV L, Chen C, Koutalos Y Mitochondria contribute to NADPH generation in mouse rod photoreceptors J Biol Chem 2014;289:1519–1528 51 Palczewski K, Jager S, Buczylko J, et al Rod outer segment retinol dehydrogenase: substrate specificity and role in phototransduction Biochemistry 1994;33:13741–13750 52 Chrispell JD, Feathers KL, Kane MA, et al Rdh12 activity and effects on retinoid processing in the murine retina J Biol Chem 2009;284:21468–21477 53 Ablonczy Z, Higbee D, Anderson DM, et al Lack of correlation between the spatial distribution of A2E and lipofuscin fluorescence in the human retinal pigment epithelium Invest Ophthalmol Vis Sci 2013;54:5535–5542 INDEX Note: Page numbers followed by “f ” indicate figures and “t ” indicate tables A ABCA4 N-Ret-PE, 421–422 PE importer, 422–423 retinal transport assays, 427 Stargardt disease, 426–427 structural features and localization, 419–421 visual cycle, 423–426 ABCA subfamily, 417–418 Acetylcholine, 230–231 Actin filament-associated protein (AFAP1), 323 Acute anterior uveitis (AAU), 284–285 Adaptive immune system HLA genes, 289 Th1 cell pathways, 289–290 Th17 cell pathways, 290–291 Treg cell pathways, 292 Adenosine, 253 Adult stem cells, 478–479 A2E See Bis-retinoid N-retinyl-Nretinylidene ethanol-amine (A2E) Age-related cataract, 212–214 Age-related macular degeneration (AMD), 374–375, 450, 480–483 Aging pigment See Lipofuscin α-Crystallins, 171–175 Amacrine and ganglion cell contributions, 259–260 AMD See Age-related macular degeneration (AMD) Angle-closure glaucoma, 316 Animal models, glaucoma age-related macular degeneration, 374–375 blood–retina and –brain barriers, 374–375 BXD strains, 372 candidate genes, 372–374, 375t death of RGCs, 371 Frank–ter Haar syndrome, 370 gene expression and correlation changes, 372, 374t genetically engineered/naturally occurring models, 367–370, 368t genetic risk factors, 366 genome-wide association mapping, 372–374 innate immunity, 372, 373f intraocular pressure, 366 Mendelian heritability, 366 MYOC Tyr437His mutation, 370 nonhuman primates, 366–367 quantitative trait loci, 372–374 retinal ganglion cells, 365–366 rodent models, 367 Wallerian degeneration, 371–372 Ankylosing spondylitis (AS), 284–285 Anterior chamber-associated immune deviation (ACAID), 345–346 Anterior cuboidal epithelial cells, 121 Antigen-presenting cells (APCs), 345–346 AQP0 protein, 123–124 Aquaporin (AQP0), 180 Aquaporin-1, 15 Area centralis, 385–386 ATP-binding cassette (ABC) transporters, 417 B Basement membrane, 64 Behcet’s disease (BD), 284–285 Beta-galactosidase (βGal), 30 βγ-Crystallins, 175–180 BFSP1, 211 BFSP2, 211 BIGH3, 74 Birdshot retinochoroidopathy (BCR), 284–285 Bis-retinoid N-retinyl-N-retinylidene ethanol-amine (A2E) animal models, 454 central pyridinium ring with amine nitrogen, 453–454 519 520 Bis-retinoid N-retinyl-N-retinylidene ethanol-amine (A2E) (Continued ) lipofuscin humans, 457–459 mice, 457 visual cycle, 452–453, 453f vitamin A, 452 Boll’s phenomenon, 434 Bone morphogenetic protein (BMP), 134 Bowman’s layer function, 13 structure, Brain-derived neurotrophic factor (BDNF) human and animal models, 494–495 retinal neuroprotection, 495 Bundle of Rochenne Duverney, 385–386 bZIP proteins, 144–146 C Carboplatin, 513–514 Cataract age-related, 212–214 congenital and infantile forms, 204 Duffy blood-group locus, 204–205 environmental risk factors, 203–204 isolated/primary inherited crystallins, 205–210 cytoskeletal proteins, 211 DNA-/RNA-binding proteins, 212 membrane proteins, 210–211 next-generation exome sequencing, 214–215 Causal genetic mutations, 85–87 Caveolins and (CAV1/CAV2), 327–328 C-C chemokine receptor type (CCR1), 290 CD See Corneal dystrophies (CD) Cellular retinaldehyde-binding protein (CRALBP), 486 Cerebrospinal fluid pressure, 332–333 CHMP4B, 210–211 Ciliary neurotrophic factor (CNTF) receptor, 350–351 11-cis-RE, 436–437 Clusterin, 89 Cold cataracts, 178 Collagen type XI, alpha1 (COL11A1), 323–324 Index Collagen type XV, alpha1 (COL15A1), 324 Collagen XVIII, alpha1 (COL18A1), 324 Cone health 11-cis-retinal generation, 467 LCA, 469–471 photoisomerization, 467 pigments and opsins, 467–468 retinoid-based chromophore, 466–467 role of retinoids, 471–473 visual cycles, 466–469, 466f Congenital hereditary endothelial dystrophy, 77 Congenital stromal dystrophy, 76 Connective tissue growth factor (CTGF), 309–310 Cornea development avascularity, 51–52 descemet membrane, 18–19 embryonic origin, 44–46 endothelium, 19–20, 47–48 epithelium, 16–17, 46–47 innervation, 49–51 stroma, 17–18, 48–49 function Bowman’s layer, 13 descemet membrane, 14–15 endothelium, 15 epithelial basement membrane, 13 epithelium, 12–13 stroma, 13–14 structure Bowman’s layer, descemet membrane, 11 endothelium, 11–12 epithelial basement membrane, 8–9 epithelium, stroma, 9–10 Corneal avascularity, 51–52 Corneal dystrophies (CD) congenital hereditary endothelial dystrophy, 77 congenital stromal dystrophy, 76 epithelial basement membrane dystrophy, 74 Fleck corneal dystrophy, 76 Fuchs endothelial cornea dystrophy, 77 gelatinous drop-like corneal dystrophy, 74 521 Index granular type 1, 75 granular type 2, 75 accumulation and degradation, 106–110 corneal fibroblasts, 102 oxidative stress, 102–106 transforming growth factor β signaling pathway, 110–111 lattice type 1, 75–76 macular corneal dytrophy, 76 Meesman corneal dystrophy, 73–74 posterior polymorphous corneal dystrophy, 77 ReisBuăcklers corneal dystrophy, 7475 Schnyder, 76 abnormal lipid metabolism, 100–101 mitochondrial changes, 101 oxidative stress, 101–102 Thiel–Behnke corneal dystrophy, 74 Corneal endothelium, 47–48 Corneal endothelium stem/progenitor cells anatomy, 34–35 characterization, 35 Corneal epithelial stem cells anatomy, 26–28 characterization, 28–29 wound healing, 29–31 Corneal epithelial wound healing basement membrane, 64 cytokine networks, 66–67 events, 63–64 growth factors, 65–66 integrins, 64–65 mesenchymal–epithelial interactions, 67–68 stages lag phase, 62 migration/reepithelialization, 63 proliferation, stratification, and differentiation, 63 Corneal epithelium, 46–47 Corneal fibroblasts, 102 Corneal innervation, 49–51 Corneal stroma, 48–49 Corneal stromal stem cells (CSSC), 33 anatomy, 31 anti-inflammatory properties, 33–34 characterization, 32 corneal tissue bioengineering, 33 niche function, 32–33 Crystallin gene expression bZIP proteins, 144–146 chick model, 142–144 c-Maf expression, 146–148 50 -distal enhancer, 146–148, 148f DNA-binding transcription factors, 144, 145t, 146f expression domain shuffling, 144–146 functions, 142, 143t gene regulatory network, 146–148 homeodomain-interacting protein kinase 2, 149 148-kb BAC clone, 149 MafA/L-Maf, 144–146 Crystallins, 123, 205–210 α-crystallins, 171–175 βγ-crystallins, 175–180 gene families, 171, 172t organelle degradation, 171 CSSC See Corneal stromal stem cells (CSSC) Cyclin-dependent kinase inhibitor 2B antisense (CDKN2BAS), 324–325, 329 Cytochrome P450, family 1, subfamily B, polypeptide (CYP1B1), 331–332 Cytokine networks, 66–67 Cytoskeletal proteins, 183–184, 211 Cytotoxic T-lymphocyte antigen (CTLA-4), 290 D Descemet membrane development, 18–19 function, 14–15 structure, 11 Dihydroceramide desaturase-1 (DES-1), 468–469 DNA-/RNA-binding proteins, 212 Dopamine, 229–230, 254, 260 E Early-onset glaucoma, 316 E-cadherin, 508 Electroretinograms (ERGs), 395, 416 Embryonic stem cells (ESCs), 478–479 522 Endoplasmic reticulum stress response, 318–321 Endothelium development, 19–20 function, 15 structure, 11–12 Energy metabolism, 184–185 En face imaging, 387–390 EPHA2, 210–211 Epidermal growth factor (EGF), 65–66 Epithelial basement membrane dystrophy, 74 function, 13 structure, 8–9 Epithelium development, 16–17 function, 12–13 structure, Exercise, retinal health animal models of retinal disease, 493 beneficial to retina and vision, 492–493 brain-derived neurotrophic factor human and animal models, 494–495 retinal neuroprotection, 495 mechanisms, 493–494 neuroprotective, 492 systemic and local pathways, 496–497 Exfoliation syndrome (XFS), 316 Experimental myopia, 274–275 Eye growth regulation choroid role, 232–235 RPE role acetylcholine, 230–231 blood–retina barrier, 225, 226f cytokines, 231–232 dopamine, 229–230 ion and fluid transport, 227–229 morphological features, 227 myopia development, 225–227 Eye morphogenesis, 400 F FCD See Fuchs corneal dystrophy (FCD) Fibronectin type III domain containing 3B (FNDC3B), 323 Fleck corneal dystrophy, 76 Fluorescence-activated cell sorting (FACS), 28–29 Index Forkhead box C1 (FOXC1), 330 Forkhead box (FOX) proteins, 17 Forkhead transcription factor (Foxc1), 52 Frank–ter Haar syndrome, 370 Fuchs corneal dystrophy (FCD) functional mechanisms epithelial-mesenchymal transition, 92 microRNA, 93 mitochondrial dysregulation, 91–92 oxidative damage and apoptosis, 89–91 unfolded protein response, 92–93 genetic basis association studies, 87–89 causal genetic mutations, 85–87 genetic linkage analysis, 84–85 structural changes Bowman’s layer, 81 descemet membrane, 82 endothelium, 83 epithelium, 81 stroma, 82 Fuchs endothelial cornea dystrophy, 77 Fundus, 384–386 FYCO1, 211 G GALK1, 213 γS-Crystallin, 178 Gap junction proteins, 181–183 Gelatinous drop-like corneal dystrophy, 74 Genetic linkage analysis, 84–85 Genome-wide association studies (GWAS) study, 271–272 Glaucoma genes and mechanisms angle-closure glaucoma, 316 cerebrospinal fluid pressure, 332–333 early-onset glaucoma, 316 endoplasmic reticulum stress response, 318–321 endothelial nitric oxide synthetase signaling and caveolae, 327–328 extracellular matrix, cell junctions, and cell adhesion AFAP1, 323 COL11A1, 323–324 COL15A1, 324 FNDC3B, 323 LOXL1, 322 523 Index LTBP2, 322 PLEKHA7, 323 genome-wide association studies, 317 lipid metabolism, 327 regulation of autophagy, 326–327 regulation of cell division CDKN2BAS, 329 GAS7, 328–329 TMCO1, 329 regulation of ocular development CYP1B1, 331–332 FOXC1, 330 LTBP2, 332 PAX6, 331 PITX2, 330–331 SIX6, 332 TGF beta signaling, 324–325 tumor necrosis factor-alpha signaling, 326 Glaucomatous neurodegeneration, 349–350 Glial fibrillary acidic protein (GFAP), 173 Glutathione, 123 Gnat1–/– mice-nonfunctional rod model, 257–258 Granular corneal dystrophy 2, 75 corneal fibroblasts, 102 oxidative stress altered antioxidant enzyme system, 105 cell death, 105–106 corneal fibroblasts and tissue, 105 mitochondrial oxidative damage, 104–105 ROS-scavenging mechanisms, 103–104 Granular type corneal dystrophy, 75 Growth arrest-specific (GAS7), 328–329 H Hepatocyte growth factor (HGF), 65–66 High myopia GWAS study, 272 Mendelian nonsyndromic, 272–273 syndromic, 273–274 HLA genes, 289 Homeodomain-interacting protein kinase (Hipk2), 149 HSF4, 212 Human lens structure, 120, 120f Hyperopia, 270–271 I Immune privilege and neuroglia, 345–348 Immune response, optic nerve and ONH astrocytes, 350–351 inflammatory responses, 353 microglia, 351–352 monocytes and regulatory T-cells, 352–353 Induced pluripotent stem cells (iPSCs), 479–480 Integrins, 64–65 Interleukins, 290 Interphotoreceptor retinol-binding protein (IRBP), 423, 436–437 Intraocular pressure (IOP) aqueous humor circulation system, 302–303 outflow resistance, 305–307 Schlemm’s canal, 304 trabecular meshwork, 303–304 trabecular outflow pathways contractile mechanisms, 307–309 POAG, 309–311 IOP See Intraocular pressure (IOP) iPSC-derived retinal pigment epithelium, 483–484 cell transplantation therapy, 483 differentiation process, 483–484, 484f personalized medicine, 484 retinoid processing, 485–486 stem cell engineering, 483 transepithelial resistance, 483–484, 485f zona occluden-1, 483–484, 485f Isolated/primary inherited cataract crystallins, 205–210 cytoskeletal proteins, 211 DNA-/RNA-binding proteins, 212 membrane proteins, 210–211 K Keratinocyte growth factor (KGF-1), 65–66 Keratocytes See Corneal fibroblasts KRT3, 73–74 KRT12, 73–74 524 L Laminin, Latent TGF-binding protein (LTBP2), 322, 332 Lattice type corneal dystrophy, 75–76 Leber congenital amaurosis (LCA), 469–471 Leber congenital amaurosis, type (LCA2), 442 Lecithin-retinol acetyltransferase (LRAT), 423, 468, 486 Lens aging, 122–124 structure and cells, 120–122 transparency, 122 Lens biology and biochemistry crystallins α-crystallins, 171–175 βγ-crystallins, 175–180 gene families, 171, 172t organelle degradation, 171 cytoskeletal proteins, 183–184 gap junction proteins, 181–183 lens metabolism energy metabolism, 184–185 osmoregulation, 187–189 reduced state maintenance, 186–187 membrane proteins, 180–181 overview, 170–171 Lens development argonaute protein 2, 152 BMP4, 150–151 embryological induction, 130–131 lens crystallins, 130–131 lens differentiation cell cycle exit, 137–141 crystallin gene expression, 142–149 lens growth and secondary lens fiber cell formation, 141–142 lens placode formation, 133–136 lens vesicle, 136–137 lentoid bodies, 152 miRNAs, 150–151 overview embryonic induction, 131–132 evo-devo approach, 133 lineage-specific DNA-binding transcription factor, 131–132 morphogenesis, 133 palisade-like morphology, 131 Index Pax6, 149–150 periocular mesenchyme, 149–150 transcriptional factories, 151–152 Lens differentiation cell cycle exit canonical cell cycle regulatory proteins, 138–139, 139t chicken embryonic explants, 139 FGF receptor genes, 139 lens capsule, 140–141 lens epithelium, 140 Sox2-expressing cells, 137–138 crystallin gene expression, 142–149 lens growth and secondary lens fiber cell formation, 141–142 Lens metabolism energy metabolism, 184–185 osmoregulation, 187–189 reduced state maintenance, 186–187 Lens placode formation, 133–136 Leukocoria, 509–510 Light-induced retinal degeneration (LIRD), 493 Limbal epithelial stem cells (LESCs), 26–28 Limbal stem cell deficiency (LSCD), 30–31 Lipid metabolism, 327 Lipofuscin A2E humans, 457–459 mice, 457 fluorescence, 450–451, 450f isolated compounds, 451–452 ocular, 452 postmitotic cells, 451 RPE, 450f, 451 Lumican (Lum), 67–68 Lysyl oxidase like (LOXL1), 322 M Macula lutea, 385–386 Macular corneal dytrophy, 76 Maf proteins, 144–146 Major intrinsic protein (MIP), 180 Matrix-assisted laser desorption–ionization (MALDI) tissue imaging mass spectrometry, 454–457 Meesman corneal dystrophy, 73–74 Melphalan, 513–514 Membrane proteins, 180–181, 210–211 525 Index Mendelian high myopia nonsyndromic, 272–273 syndromic, 273–274 Mesenchymal–epithelial interactions, 67–68 Mesenchyme-to-epithelial transition, 47 MicroRNA (miRNA), 93 MiR-146a, 292 Mitomycin C, 110 Molecular genetics hyperopia, 270–271 myopia genetic loci, 271–272 GWAS study, 271–272 human variants, 274–275 loci/genes, 272–274 refraction, 269–270 whole-genome analysis, 275 Monoclonal antibody (MAb), 437 Mouse models, LCA, 469471 Muăller glial cell (MG), 397399 Multipotent stem cells, 479 Myocilin (MYOC), 318–321 Myopia dopamine, 254 form-deprivation, 256–257 genetic loci, 271–272 GWAS study, 271–272 human variants, 274–275 loci/genes, 272–274 photoreceptor input, 255–258 ocular growth (see Eye growth regulation) ON and OFF pathway contributions, 258–259 Myopic sclera See Scleral mechanisms N Nance–Horan syndrome, 211 N-cadherin, 47–48, 180 Neural-cell adhesion molecule (NCAM 2), 180 Neural crest cells, 45 Neuroglial cells astrocytes, 347348 microglia, 347 Muăller glia, 348 Neuroinflammation glaucomatous neurodegeneration, 349–350 immune privilege and neuroglia, 345–348 immune response in optic nerve and ONH astrocytes, 350–351 inflammatory responses, 353 microglia, 351–352 monocytes and regulatory T-cells, 352–353 intraocular pressure, 344 laser-induced trabeculoplasty, 344–345 retina astrocytes, 354 dendritic cells, 356 inflammatory responses, 356–357 microglia, 354355 Muăller glia, 355356 retinal ganglion cell death, 344 Nidogens, Nitric oxide, 253254 Non-neuronal glial Muăller cells, 34 Nonsyndromic high myopia, 272–273 N-retinylidene-phosphatidylethanolamine (N-ret-PE), 418, 421–423 Nucleotide binding domains (NBDs), 417 Nyxnob/nob mice-ON pathway defect model, 258–259 O Ocular lipofuscin, 452 Ocular/systemic diseases, 273–274 Opsins, 467–468 Optic nerve and optic nerve head (ONH) astrocytes, 350–351 inflammatory responses, 353 microglia, 351–352 monocytes and regulatory T-cells, 352–353 Optineurin (OPTN), 326–327 Osmoregulation, 187–189 Osteopontin, 291 Outer segment disk genesis and shedding, 391–393 P Paired box (PAX6), 331 Paired-like homeodomain (PITX2), 330–331 Peripheral myelin protein-22 (PMP22), 210 Peroxiredoxins, 90 526 Persistent retinal neurogenesis and regeneration, 406–408 Pgc1alpha, 495–496, 497f P-glycoprotein, 419 Phosphatidyl-ethanolamine (PE), 418, 422–423 Photoreceptor neurogenesis, 405–406 PITX3, 212 Plasmalemma vesicle associated protein (PLVAP), 304 Pleckstrin homology domain-containing protein (PLEKHA7), 323 Pluripotent stem cells, 479 Posterior polymorphous corneal dystrophy, 77 Primary open-angle glaucoma (POAG), 309–311 Proinflammatory interleukin 1α, 66–67 Protein degradation systems, 106–108 R Raldh2/Aldh1a2 enzymes, 136 RB1 gene, 504–506 Rb protein, 504–506, 507f rd1–/– and rd10–/– mice-photoreceptor degeneration models, 255–257 Refraction animal studies, 223–225 error, 222 genetic contribution, 269–270 human variants, experimental myopia, 274–275 molecular genetics of hyperopia, 270–271 of myopia, 271–274 and retina (see Retina on refraction) ReisBuăcklers corneal dystrophy, 7475 Retina blood supply, 387 circuitry, 393 en face imaging and patterns, 387–390 fundus, 384–386 neuroinflammation astrocytes, 354 dendritic cells, 356 inflammatory responses, 356–357 microglia, 354–355 Muăller glia, 355356 nobel prizes, 394395 Index outer segment disk genesis and shedding, 391–393 structure, cross-section, 386–387 visual transduction cascade, 390–391 Retinal circuitry, 393 Retinal ganglion cells (RGCs), 365–366 Retinal neurogenesis, 400–402 Retinal neuronal diversity extrinsic factors, 402–404, 404t intrinsic factors, 402, 403t photoreceptor neurogenesis, 405–406 RGC neurogenesis, 404–405 Retinal pigment epithelium (RPE) acetylcholine, 230–231 blood–retina barrier, 225, 226f cytokines, 231–232 dopamine, 229–230 ion and fluid transport, 227–229 morphological features, 227 Retinal progenitor/precursor cell (RPC), 510–511 Retina on refraction amacrine and ganglion cell contributions, 259–260 anatomy and circuitry, 250, 250f dopamine modulation, 260 form-deprivation myopia, 260–261 mouse, 252–253 neurotransmitters, 253–254 normal and visually deprived refractive development, 260–261 ocular growth, 251–252 ON and OFF pathway contributions Nyxnob/nob mice-ON pathway defect model, 258–259 Vsx1–/– mice - OFF pathway defect model, 259 photoreceptor input to myopia Gnat1–/– mice - nonfunctional rod model, 257–258 rd1–/– and rd10–/– mice-photoreceptor degeneration models, 255–257 retinal cells and neurotransmitters, 250–251 Retinoblastoma clinical features, 509–510 clinical genetics, 504 management, 512–514 527 Index pathology, 510–512 preclinical models, 508–509 RB1 gene, 504–506 secondary mutations, 506–508 tumorigenesis, 503–504 Retinocytoma, 506–508, 507f, 512, 513f Retinoic acid (RA) signaling, 134 Retinoid-based chromophore, 466–467 Retinoids, 391–393 Retinol dehydrogenases (RDHs), 423 RGC neurogenesis, 404–405 Rod lineage, 406–408 RPE65 gene disease associations, 442–444 structure, function, and biochemical mechanism BCMO1, 438 11-cis-retinol dehydrogenase, 438–440 electron delocalization, 441 human embryonic kidney cells, 438 hydrophobic retinoids, 441–442 iron cofactor, 441 palmitoylation, 440 tertiary structure, 438–440, 440f 30 -untranslated region, 437–438 S Schlemm’s canal, 304 Schnyder CD, 76 abnormal lipid metabolism, 100–101 mitochondrial changes, 101 oxidative stress, 101–102 Scleral mechanisms animal models, 243–244 biomechanical properties, 244 collagen-specific miRNAs, 244–245 extracellular matrix, 241–242 genetic susceptibility, 245–246 genome-wide gene expression profiles, 244 guinea pig model, 243–244 structural and biomechanical changes, 242–243 topical atropine, 245 tree shrew model, 243–244 Semaphorin3A (Sema3A), 50–51 Signal transducer and activator of transcription protein (STAT4), 289–290 SIX Homeobox (SIX6), 332 Small heat-shock protein (sHSP), 205–210 Stargardt disease, 426–427 Stem cells age-related macular degeneration, 480–483 clustered, regularly interspaced short palindromic repeats, 486–487 corneal endothelium anatomy, 34–35 characterization, 35 corneal epithelial anatomy, 26–28 characterization, 28–29 wound healing, 29–31 CSSC, 33 anatomy, 31 anti-inflammatory properties, 33–34 characterization, 32 corneal tissue bioengineering, 33 niche function, 32–33 definitions and types, 478–479 iPSCs, 479–480 retinal pigment epithelium, 480–483 visual cycle, 480–483 Strabismus, 509–510 Stroma development, 17–18 function, 13–14 structure, 9–10 Syndromic high myopia, 273–274 T Tank-binding kinase (TBK1), 326–327 Taxon-specific crystallins, 178–179 TGF beta signaling, 324–325 TGFBI, 74 TGFBIp See Transforming growth factor β-induced protein (TGFBIp) TGF-β1 protein, 89 Th1 cell pathways, 289–290 Th17 cell pathways, 290–291 Thiel-Behnke corneal dystrophy, 74 Topotecan, 513–514 Totipotent stem cells, 479 Trabecular meshwork, 303–304 Trabecular outflow pathways contractile mechanisms, 307–309 POAG, 309–311 528 Transducin, 390–391 Transforming growth factor β-induced protein (TGFBIp) accumulation and degradation autophagy suppression, 108 effect of activated autophagy, 109–110 insufficient autophagy, 108 mitomycin C, 110 protein degradation systems, 106–108 therapeutic applications lithium, 111 transforming growth factor β signaling pathway, 110–111 Transmembrane and coiled-coil domains-1 (TMCO1), 329 Transmembrane domains (TMDs), 417 Transparency, 122 Treg cell pathways, 292 TrkB receptor, 495 Tumor necrosis factor-alpha signaling, 326 Tumor necrosis factor receptor-associated factor (TRAF), 291 U UbiA prenyltransferase domain-containing (UBIAD1) gene, 99–100 Ubiquitin/proteasome system (UPS), 106–107 Uveitis adaptive immune system HLA genes, 289 Th1 cell pathways, 289–290 Th17 cell pathways, 290–291 Treg cell pathways, 292 Behcet’s disease, 284–285 copy number variants, 292–293 definition, 284 immune response, 285 innate immune system, 286–288 Index histology and cell arrangements, 397399, 398f Muăller glial cell, 397399 persistent retinal neurogenesis and regeneration, 406–408 retinal neurogenesis, 400–402 retinal neuronal diversity extrinsic factors, 402–404, 404t intrinsic factors, 402, 403t photoreceptor neurogenesis, 405–406 RGC neurogenesis, 404–405 tissue formation, 397–399, 399f zebrafish model, 399 Vimentin, 183–184 Visual cycle ABCA4, 423–426 history, 434–437 RPE65 disease associations, 442–444 structure, function, and biochemical mechanism, 437–442 Visual system anterior and posterior segments, 1, 2f cones, 3–4 nuclear layers, 3–4 oculomotor system, refractive index, 1–2 rods, 3–4 RPE cells, 2–3 vertebrate retina, 2–3, 3f Vitamin A, 468 Vogt–Koyanagi–Harada (VKH) syndrome, 284–285 Vsx1–/– mice - OFF pathway defect model, 259 W Wallerian degeneration, 371 Wound healing, 29–31 V Z Vertebrate eye and retina eye morphogenesis, 400 ZEB protein, 508 Zona occluden-1 (ZO-1), 483–484, 485f ... strong affinity to laminin and collagen IV.4 Nidogen-1 and Nidogen-2 each demonstrate distinct binding sites to collagen IV and laminin, respectively, reflected in inhibition assays and studies... metallothionein, and integrin alpha9, whereas basal cells Overview of the Cornea 13 of the corneal epithelium specifically stain for K3 and K12, Connexin 43, involucrin, P-cadherin, nestin, and integrins... scarring and vision impairment In fact, millions of people around the world suffer from corneal scars resulting in the loss of vision.1 Progress in Molecular Biology and Translational Science, Volume