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Medecine Sciences : M/S 2020The neuroretina is a functional unit of the central nervous system that converts a light signal into a nerve impulse. Of neuroectodermal origin, derived from the... (Review)
Review
The neuroretina is a functional unit of the central nervous system that converts a light signal into a nerve impulse. Of neuroectodermal origin, derived from the diencephalon, the neuroretina is a layered tissue composed of six types of neuronal cells (two types of photoreceptors: cones and rods, horizontal, bipolar, amacrine and ganglion cells) and three types of glial cells (Müller glial cells, astrocytes and microglial cells). The neuroretina lays on the retinal pigmentary epithelium, that together form the retina. The existence of the internal and external blood-retinal barriers and intra-retinal junctions reflects the fineness of regulation of the retinal exchanges with the circulation and within the retina itself. The central zone of the human retina, which is highly specialized for visual acuity, has anatomical specificities. Recent imaging methods make it possible now to enrich our knowledge of the anatomical and functional characteristics of the retina, which are still imperfectly described.
Topics: Animals; Choroid; Humans; Neuroglia; Retina; Retinal Cone Photoreceptor Cells; Retinal Pigment Epithelium; Retinal Rod Photoreceptor Cells; Retinal Vessels
PubMed: 32614310
DOI: 10.1051/medsci/2020094 -
Developmental Cell May 2020The development of single-cell RNA sequencing (scRNA-seq) has allowed high-resolution analysis of cell-type diversity and transcriptional networks controlling cell-fate...
The development of single-cell RNA sequencing (scRNA-seq) has allowed high-resolution analysis of cell-type diversity and transcriptional networks controlling cell-fate specification. To identify the transcriptional networks governing human retinal development, we performed scRNA-seq analysis on 16 time points from developing retina as well as four early stages of retinal organoid differentiation. We identified evolutionarily conserved patterns of gene expression during retinal progenitor maturation and specification of all seven major retinal cell types. Furthermore, we identified gene-expression differences between developing macula and periphery and between distinct populations of horizontal cells. We also identified species-specific patterns of gene expression during human and mouse retinal development. Finally, we identified an unexpected role for ATOH7 expression in regulation of photoreceptor specification during late retinogenesis. These results provide a roadmap to future studies of human retinal development and may help guide the design of cell-based therapies for treating retinal dystrophies.
Topics: Aged, 80 and over; Animals; Basic Helix-Loop-Helix Transcription Factors; Biological Evolution; Cell Differentiation; Female; Gene Expression Regulation, Developmental; Humans; Mice; Organogenesis; Retina; Retinal Cone Photoreceptor Cells; Single-Cell Analysis; Species Specificity
PubMed: 32386599
DOI: 10.1016/j.devcel.2020.04.009 -
International Journal of Molecular... Apr 2023Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies characterized by the degeneration of rod photoreceptors, followed by the degeneration of... (Review)
Review
Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies characterized by the degeneration of rod photoreceptors, followed by the degeneration of cone photoreceptors. As a result of photoreceptor degeneration, affected individuals experience gradual loss of visual function, with primary symptoms of progressive nyctalopia, constricted visual fields and, ultimately, central vision loss. The onset, severity and clinical course of RP shows great variability and unpredictability, with most patients already experiencing some degree of visual disability in childhood. While RP is currently untreatable for the majority of patients, significant efforts have been made in the development of genetic therapies, which offer new hope for treatment for patients affected by inherited retinal dystrophies. In this exciting era of emerging gene therapies, it remains imperative to continue supporting patients with RP using all available options to manage their condition. Patients with RP experience a wide variety of physical, mental and social-emotional difficulties during their lifetime, of which some require timely intervention. This review aims to familiarize readers with clinical management options that are currently available for patients with RP.
Topics: Humans; Retinitis Pigmentosa; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Night Blindness; Retinal Dystrophies
PubMed: 37108642
DOI: 10.3390/ijms24087481 -
Revue Medicale de Liege Feb 2020Retinitis pigmentosa is the most frequent hereditary dystrophy of the retina, with a global prevalence of 1/4.000. The underlying mechanism involves progressive loss,...
Retinitis pigmentosa is the most frequent hereditary dystrophy of the retina, with a global prevalence of 1/4.000. The underlying mechanism involves progressive loss, first of the rod photoreceptor cells, followed by the cone photoreceptor cells. Finally, complete blindness may occur. Genetic transmission is known but most cases are sporadic. Few effective treatments exist nowadays and hence regular follow-up is required in a revalidation center.
Topics: Humans; Retina; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Retinitis Pigmentosa
PubMed: 32030928
DOI: No ID Found -
International Journal of Molecular... Apr 2021Inherited retinal dystrophies (IRDs) are a group of rare eye diseases caused by gene mutations that result in the degradation of cone and rod photoreceptors or the... (Review)
Review
Inherited retinal dystrophies (IRDs) are a group of rare eye diseases caused by gene mutations that result in the degradation of cone and rod photoreceptors or the retinal pigment epithelium. Retinal degradation progress is often irreversible, with clinical manifestations including color or night blindness, peripheral visual defects and subsequent vision loss. Thus, gene therapies that restore functional retinal proteins by either replenishing unmutated genes or truncating mutated genes are needed. Coincidentally, the eye's accessibility and immune-privileged status along with major advances in gene identification and gene delivery systems heralded gene therapies for IRDs. Among these clinical trials, voretigene neparvovec-rzyl (Luxturna), an adeno-associated virus vector-based gene therapy drug, was approved by the FDA for treating patients with confirmed biallelic mutation-associated Leber Congenital Amaurosis (LCA) in 2017. This review includes current IRD gene therapy clinical trials and further summarizes preclinical studies and therapeutic strategies for LCA, including adeno-associated virus-based gene augmentation therapy, 11-cis-retinal replacement, RNA-based antisense oligonucleotide therapy and CRISPR-Cas9 gene-editing therapy. Understanding the gene therapy development for LCA may accelerate and predict the potential hurdles of future therapeutics translation. It may also serve as the template for the research and development of treatment for other IRDs.
Topics: Dependovirus; Eye Proteins; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Leber Congenital Amaurosis; Mutation; RNA; Retina; Retinal Cone Photoreceptor Cells; Retinal Dystrophies
PubMed: 33926102
DOI: 10.3390/ijms22094534 -
Proceedings of the National Academy of... May 2023Temporal identity factors are sufficient to reprogram developmental competence of neural progenitors and shift cell fate output, but whether they can also reprogram the...
Temporal identity factors are sufficient to reprogram developmental competence of neural progenitors and shift cell fate output, but whether they can also reprogram the identity of terminally differentiated cells is unknown. To address this question, we designed a conditional gene expression system that allows rapid screening of potential reprogramming factors in mouse retinal glial cells combined with genetic lineage tracing. Using this assay, we found that coexpression of the early temporal identity transcription factors Ikzf1 and Ikzf4 is sufficient to directly convert Müller glial (MG) cells into cells that translocate to the outer nuclear layer (ONL), where photoreceptor cells normally reside. We name these "induced ONL (iONL)" cells. Using genetic lineage tracing, histological, immunohistochemical, and single-cell transcriptome and multiome analyses, we show that expression of Ikzf1/4 in MG in vivo, without retinal injury, mostly generates iONL cells that share molecular characteristics with bipolar cells, although a fraction of them stain for Rxrg, a cone photoreceptor marker. Furthermore, we show that coexpression of Ikzf1 and Ikzf4 can reprogram mouse embryonic fibroblasts to induced neurons in culture by rapidly remodeling chromatin and activating a neuronal gene expression program. This work uncovers general neuronal reprogramming properties for temporal identity factors in terminally differentiated cells.
Topics: Animals; Mice; Fibroblasts; Retina; Retinal Cone Photoreceptor Cells; Transcription Factors; Cell Differentiation; Cellular Reprogramming
PubMed: 37126716
DOI: 10.1073/pnas.2122168120 -
Pflugers Archiv : European Journal of... Sep 2021In the vertebrate retina, signals generated by cones of different spectral preference and by highly sensitive rod photoreceptors interact at various levels to extract... (Review)
Review
In the vertebrate retina, signals generated by cones of different spectral preference and by highly sensitive rod photoreceptors interact at various levels to extract salient visual information. The first opportunity for such interaction is offered by electrical coupling of the photoreceptors themselves, which is mediated by gap junctions located at the contact points of specialised cellular processes: synaptic terminals, telodendria and radial fins. Here, we examine the evolutionary pressures for and against interphotoreceptor coupling, which are likely to have shaped how coupling is deployed in different species. The impact of coupling on signal to noise ratio, spatial acuity, contrast sensitivity, absolute and increment threshold, retinal signal flow and colour discrimination is discussed while emphasising available data from a variety of vertebrate models spanning from lampreys to primates. We highlight the many gaps in our knowledge, persisting discrepancies in the literature, as well as some major unanswered questions on the actual extent and physiological role of cone-cone, rod-cone and rod-rod communication. Lastly, we point toward limited but intriguing evidence suggestive of the ancestral form of coupling among ciliary photoreceptors.
Topics: Animals; Gap Junctions; Humans; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Synapses
PubMed: 33988778
DOI: 10.1007/s00424-021-02572-9 -
Pflugers Archiv : European Journal of... Sep 2021Cone photoreceptors provide the foundation of most of human visual experience, but because they are smaller and less numerous than rods in most mammalian retinas, much... (Review)
Review
Cone photoreceptors provide the foundation of most of human visual experience, but because they are smaller and less numerous than rods in most mammalian retinas, much less is known about their physiology. We describe new techniques and approaches which are helping to provide a better understanding of cone function. We focus on several outstanding issues, including the identification of the features of the phototransduction cascade that are responsible for the more rapid kinetics and decreased sensitivity of the cone response, the roles of inner-segment voltage-gated and Ca-activated channels, the means by which cones remain responsive even in the brightest illumination, mechanisms of cone visual pigment regeneration in constant light, and energy consumption of cones in comparison to that of rods.
Topics: Animals; Calcium; Humans; Photic Stimulation; Retinal Cone Photoreceptor Cells; Vision, Ocular
PubMed: 33742309
DOI: 10.1007/s00424-021-02551-0 -
Experimental Eye Research Dec 2020Bilallelic variants in the USH2A gene can cause Usher syndrome type 2 and non-syndromic retinitis pigmentosa. In both disorders, the retinal phenotype involves... (Review)
Review
Bilallelic variants in the USH2A gene can cause Usher syndrome type 2 and non-syndromic retinitis pigmentosa. In both disorders, the retinal phenotype involves progressive rod photoreceptor loss resulting in nyctalopia and a constricted visual field, followed by subsequent cone degeneration, leading to the loss of central vision and severe visual impairment. The USH2A gene raises many challenges for researchers and clinicians due to a broad spectrum of mutations, a large gene size hampering gene therapy development and limited knowledge on its pathogenicity. Patients with Usher type 2 may benefit from hearing aids or cochlear implants to correct their hearing defects, but there are currently no approved treatments available for the USH2A-retinopathy. Several treatment strategies, including antisense oligonucleotides and translational readthrough inducing drugs, have shown therapeutic promise in preclinical studies. Further understanding of the pathogenesis and natural history of USH2A-related disorders is required to develop innovative treatments and design clinical trials based on reliable outcome measures. The present review will discuss the current knowledge about USH2A, the emerging therapeutics and existing challenges.
Topics: DNA; DNA Mutational Analysis; Disease Management; Electroretinography; Extracellular Matrix Proteins; Genotype; Humans; Mutation; Phenotype; Retinal Cone Photoreceptor Cells; Retinal Diseases
PubMed: 33121974
DOI: 10.1016/j.exer.2020.108330 -
Current Opinion in Pharmacology Aug 2022Blinding diseases that are caused by degeneration of rod and cone photoreceptor cells often spare the rest of the retinal circuit, from bipolar cells, which are directly... (Review)
Review
Blinding diseases that are caused by degeneration of rod and cone photoreceptor cells often spare the rest of the retinal circuit, from bipolar cells, which are directly innervated by photoreceptor cells, to the output ganglion cells that project axons to the brain. A strategy for restoring vision is to introduce light sensitivity to the surviving cells of the retina. One approach is optogenetics, in which surviving cells are virally transfected with a gene encoding a signaling protein that becomes sensitive to light by binding to the biologically available chromophore retinal, the same chromophore that is used by the opsin photo-detectors of rods and cones. A second approach uses photopharmacology, in which a synthetic photoswitch associates with a native or engineered ion channel or receptor. We review these approaches and look ahead to the next generation of advances that could reconstitute core aspects of natural vision.
Topics: Humans; Optogenetics; Retina; Retinal Cone Photoreceptor Cells; Rod Opsins
PubMed: 35749908
DOI: 10.1016/j.coph.2022.102259