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Advances in Experimental Medicine and... 2010The outer segments of photoreceptor cells are specialized sensory cilia, and share many features with other primary and sensory cilia. Like other cilia, photoreceptor... (Review)
Review
The outer segments of photoreceptor cells are specialized sensory cilia, and share many features with other primary and sensory cilia. Like other cilia, photoreceptor sensory cilium (PSC) comprises a membrane domain of outer segment and its cytoskeleton. We have recently identified the protein components of mouse PSCs, and found that the list of PSC proteins, called the PSC proteome, contains many novel cilia proteins. Studies have shown that many of the identified retinal degeneration disease genes encode proteins which are part of the PSC. Furthermore, mutations in genes encoding proteins expressed both in photoreceptors and other cilia result in systemic diseases, such as Usher syndrome, Bardet-Biedl syndrome (BBS), and Senior-Loken syndrome that involve retinal degeneration along with other disorders consequent to cilia dysfunction such as deafness and polycystic kidney disease. Based on these findings, we hypothesize that genes that encode proteins required for formation of PSCs are good candidate retinal degeneration disease genes. This chapter will summarize our studies on identifying novel PSC proteins from the PSC proteome. As an example of these studies, we demonstrated that tetratricopeptide the repeat domain 21B (TTC21B) protein is a novel PSC protein and is required for normal cilia formation in primary and photoreceptor sensory cilia.
Topics: Animals; Eye Proteins; Genetic Diseases, Inborn; Humans; Mutation; Photoreceptor Cells; Proteome; Retinal Degeneration
PubMed: 20238021
DOI: 10.1007/978-1-4419-1399-9_26 -
Current Biology : CB Feb 2011
Topics: Animal Communication; Animals; Light; Photoreceptor Cells, Invertebrate; Photoreceptor Cells, Vertebrate; Vision, Ocular
PubMed: 21300269
DOI: 10.1016/j.cub.2010.12.012 -
Eye (London, England) Nov 2021In human retina, photoreceptor cell death (PCD) is a slow but conspicuous event, which continues with aging. Rods die earlier than cones, the latter continue to alter in... (Review)
Review
In human retina, photoreceptor cell death (PCD) is a slow but conspicuous event, which continues with aging. Rods die earlier than cones, the latter continue to alter in a subtle manner until advanced aging. This review summarizes the existing information on age-related changes in photoreceptor cells, especially cones and analyses the possible associated factors. Oxidative and nitrosative stress are involved in photoreceptor alterations, which may stem from light and iron toxicity and other sources. Lipid peroxidation in macular photoreceptor outer segments and mitochondrial aberrations are prominent in aging. It is important to understand how those changes ultimately trigger PCD. The redistribution of calbindin D-28K and long/middle-wavelength-sensitive opsin in the parafoveal and perifoveal cones, anomalies in their somata and axons are strong predictors of their increasing vulnerability with aging. Signs of reduced autophagy, with autophagosomes containing organelle remnants are seen in aging photoreceptor cells. Currently, mechanisms that lead to human PCD are unknown; some observations favour apoptosis as a pathway. Since cones appear to change slowly, there is an opportunity to reverse those changes before they die. Therefore, a full understanding of how cones alter and the molecular pathways they utilize for survival must be the future research goal. Recent approaches to prevent PCD in aging and diseases are highlighted.
Topics: Aging; Humans; Immunohistochemistry; Retina; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells
PubMed: 34079093
DOI: 10.1038/s41433-021-01602-1 -
Current Opinion in Cell Biology Oct 2014Optogenetics, the use of genetically encoded tools to control protein function with light, can generate localized changes in signaling within living cells and animals.... (Review)
Review
Optogenetics, the use of genetically encoded tools to control protein function with light, can generate localized changes in signaling within living cells and animals. For years it has been focused on channel proteins for neurobiology, but has recently expanded to cover many different types of proteins, using a broad array of different protein engineering approaches. These methods have largely been directed at proteins involved in motility, cytoskeletal regulation and gene expression. This review provides a survey of non-channel proteins that have been engineered for optogenetics. Existing molecules are used to illustrate the advantages and disadvantages of the many imaginative new approaches that the reader can use to create light-controlled proteins.
Topics: Animals; Cell Movement; Humans; Light; Optogenetics; Oxygen; Photoreceptor Cells; Phytochrome; Signal Transduction
PubMed: 25216352
DOI: 10.1016/j.ceb.2014.08.004 -
Stem Cell Research & Therapy Aug 2021Retinal regenerative therapies hold great promise for the treatment of inherited retinal degenerations (IRDs). Studies in preclinical lower mammal models of IRDs have...
BACKGROUND
Retinal regenerative therapies hold great promise for the treatment of inherited retinal degenerations (IRDs). Studies in preclinical lower mammal models of IRDs have suggested visual improvement following retinal photoreceptor precursors transplantation, but there is limited evidence on the ability of these transplants to rescue retinal damage in higher mammals. The purpose of this study was to evaluate the therapeutic potential of photoreceptor precursors derived from clinically compliant induced pluripotent stem cells (iPSCs).
METHODS
Photoreceptor precursors were sub-retinally transplanted into non-human primates (Macaca fascicularis). The cells were transplanted both in naïve and cobalt chloride-induced retinal degeneration models who had been receiving systemic immunosuppression for one week prior to the procedure. Optical coherence tomography, fundus autofluorescence imaging, electroretinography, ex vivo histology and immunofluorescence staining were used to evaluate retinal structure, function and survival of transplanted cells.
RESULTS
There were no adverse effects of iPSC-derived photoreceptor precursors on retinal structure or function in naïve NHP models, indicating good biocompatibility. In addition, photoreceptor precursors injected into cobalt chloride-induced retinal degeneration NHP models demonstrated an ability both to survive and to mature into cone photoreceptors at 3 months post-transplant. Optical coherence tomography showed restoration of retinal ellipsoid zone post-transplantation.
CONCLUSIONS
These findings demonstrate the safety and therapeutic potential of clinically compliant iPSC-derived photoreceptor precursors as a cell replacement source for future clinical trials.
Topics: Animals; Humans; Induced Pluripotent Stem Cells; Photoreceptor Cells, Vertebrate; Primates; Retinal Cone Photoreceptor Cells; Retinal Degeneration
PubMed: 34412697
DOI: 10.1186/s13287-021-02539-8 -
Scientific Reports Sep 2021Vertebrate photoreceptors contain large numbers of closely-packed mitochondria which sustain the high metabolic demands of these cells. These mitochondria populations...
Vertebrate photoreceptors contain large numbers of closely-packed mitochondria which sustain the high metabolic demands of these cells. These mitochondria populations are dynamic and undergo fusion and fission events. This activity serves to maintain the population in a healthy state. In the event of mitochondrial damage, sub-domains, or indeed whole mitochondria, can be degraded and population homeostasis achieved. If this process is overwhelmed cell death may result. Death of photoreceptors contributes to loss of vision in aging individuals and is associated with many eye diseases. In this study we used serial block face scanning electron microscopy of adult Macaca fascicularis retinae to examine the 3D structure of mitochondria in rod and cone photoreceptors. We show that healthy-looking photoreceptors contain mitochondria exhibiting a range of shapes which are associated with different regions of the cell. In some photoreceptors we observe mitochondrial swelling and other changes often associated with cellular stress. In rods and cones that appear stressed we identify elongated domains of mitochondria with densely-packed normal cristae associated with photoreceptor ciliary rootlet bundles. We observe mitochondrial fission and mitochondrion fragments localised to these domains. Swollen mitochondria with few intact cristae are located towards the periphery of the photoreceptor inner-segment in rods, whilst they are found throughout the cell in cones. Swollen mitochondria exhibit sites on the mitochondrial inner membrane which have undergone complex invagination resulting in membranous, electron-dense aggregates. Membrane contact occurs between the mitochondrion and the photoreceptor plasma membrane in the vicinity of these aggregates, and a series of subsequent membrane fusions results in expulsion of the mitochondrial aggregate from the photoreceptor. These events are primarily associated with rods. The potential fate of this purged material and consequences of its clearance by retinal pigment epithelia are discussed.
Topics: Animals; Cell Membrane; Imaging, Three-Dimensional; Macaca fascicularis; Microscopy, Electron, Scanning; Mitochondria; Mitochondrial Membranes; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells
PubMed: 34552195
DOI: 10.1038/s41598-021-98409-7 -
Molecular Endocrinology (Baltimore, Md.) Jun 2012Rod and cone photoreceptors are specialized sensory cells that mediate vision. Transcriptional controls are critical for the development and long-term survival of... (Review)
Review
Rod and cone photoreceptors are specialized sensory cells that mediate vision. Transcriptional controls are critical for the development and long-term survival of photoreceptors; when these controls become ineffective, retinal dysfunction or degenerative disease may result. This review discusses the role of nuclear receptors, a class of ligand-regulated transcription factors, at key stages of photoreceptor life in the mammalian retina. Nuclear receptors with known ligands, such as retinoids or thyroid hormone, together with several orphan receptors without identified physiological ligands, complement other classes of transcription factors in directing the differentiation and functional maintenance of photoreceptors. The potential of nuclear receptors to respond to ligands introduces versatility into the control of photoreceptor development and function and may suggest new opportunities for treatments of photoreceptor disease.
Topics: Animals; Cell Differentiation; Eye Diseases; Gene Expression Regulation; Humans; Ligands; Mutation; Phenotype; Photoreceptor Cells; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Vision, Ocular
PubMed: 22556342
DOI: 10.1210/me.2012-1010 -
Photochemical & Photobiological... Oct 2015In the past few decades, fluorescent proteins have revolutionized the field of cell biology. Phototransformable fluorescent proteins are capable of changing their... (Review)
Review
In the past few decades, fluorescent proteins have revolutionized the field of cell biology. Phototransformable fluorescent proteins are capable of changing their excitation and emission spectra after being exposed to specific wavelength(s) of light. The majority of phototransformable fluorescent proteins have originated from marine organisms. Genetic engineering of these proteins has made available many choices for different colors, modes of conversion, and other biophysical properties. Their phototransformative property has allowed the highlighting and tracking of subpopulations of cells, organelles, and proteins in living systems. Furthermore, phototransformable fluorescent proteins have offered new methods for superresolution fluorescence microscopy and optogenetics manipulation of proteins. One of the major advantages of phototransformable fluorescent proteins is their applicability for visualizing newly synthesized proteins that are en route to their final destinations. In this paper, we will discuss the biological applications of phototransformable fluorescent proteins with special emphasis on the application of tracking membrane proteins in vertebrate photoreceptor cells.
Topics: Animals; Biosensing Techniques; Cells; Humans; Light; Luminescent Proteins; Photoreceptor Cells
PubMed: 26345171
DOI: 10.1039/c5pp00174a -
The Keio Journal of Medicine Sep 1996There is increasing evidence that soluble polypeptide growth factors such as those belonging to the fibroblast growth factor (FGF) family play important roles in many... (Review)
Review
There is increasing evidence that soluble polypeptide growth factors such as those belonging to the fibroblast growth factor (FGF) family play important roles in many aspects of photoreceptor cell biology, including differentiation, continued survival and pathology. At least two members of this family, acidic FGF and basic FGF, are synthesized by, bind to and have profound effects upon these highly specialized retinal first-order neurons. The present review presents an overview of the evidence accumulated to date and will try to suggest future directions for research.
Topics: Animals; Cell Differentiation; Cell Survival; Fibroblast Growth Factors; Humans; Models, Neurological; Photoreceptor Cells
PubMed: 8897757
DOI: 10.2302/kjm.45.140 -
ELife Jul 2023The first steps of vision take place within a stack of tightly packed disc-shaped membranes, or 'discs', located in the outer segment compartment of photoreceptor cells....
The first steps of vision take place within a stack of tightly packed disc-shaped membranes, or 'discs', located in the outer segment compartment of photoreceptor cells. In rod photoreceptors, discs are enclosed inside the outer segment and contain deep indentations in their rims called 'incisures'. The presence of incisures has been documented in a variety of species, yet their role remains elusive. In this study, we combined traditional electron microscopy with three-dimensional electron tomography to demonstrate that incisures are formed only after discs become completely enclosed. We also observed that, at the earliest stage of their formation, discs are not round as typically depicted but rather are highly irregular in shape and resemble expanding lamellipodia. Using genetically manipulated mice and frogs and measuring outer segment protein abundances by quantitative mass spectrometry, we further found that incisure size is determined by the molar ratio between peripherin-2, a disc rim protein critical for the process of disc enclosure, and rhodopsin, the major structural component of disc membranes. While a high perpherin-2 to rhodopsin ratio causes an increase in incisure size and structural complexity, a low ratio precludes incisure formation. Based on these data, we propose a model whereby normal rods express a modest excess of peripherin-2 over the amount required for complete disc enclosure in order to ensure that this important step of disc formation is accomplished. Once the disc is enclosed, the excess peripherin-2 incorporates into the rim to form an incisure.
Topics: Animals; Mice; Rhodopsin; Peripherins; Rod Cell Outer Segment; Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Vision, Ocular
PubMed: 37449984
DOI: 10.7554/eLife.89160