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Advances in Experimental Medicine and... 2020Primary cilia are microtubule-based sensory organelles that are involved in the organization of numerous key signals during development and in differentiated tissue... (Review)
Review
Primary cilia are microtubule-based sensory organelles that are involved in the organization of numerous key signals during development and in differentiated tissue homeostasis. In fact, the formation and resorption of cilia highly depends on the cell cycle phase in replicative cells, and the ubiquitin proteasome pathway (UPS) proteins, such as E3 ligases and deubiquitinating enzymes, promote microtubule assembly and disassembly by regulating the degradation/availability of ciliary regulatory proteins. Also, many differentiated tissues display cilia, and mutations in genes encoding ciliary proteins are associated with several human pathologies, named ciliopathies, which are multi-organ rare diseases. The retina is one of the organs most affected by ciliary gene mutations because photoreceptors are ciliated cells. Photoreception and phototransduction occur in the outer segment, a highly specialized neurosensory cilium. In this review, we focus on the function of UPS proteins in ciliogenesis and cilia length control in replicative cells and compare it with the scanty data on the identified UPS genes that cause syndromic and non-syndromic inherited retinal disorders. Clearly, further work using animal models and gene-edited mutants of ciliary genes in cells and organoids will widen the landscape of UPS involvement in ciliogenesis and cilia homeostasis.
Topics: Animals; Cilia; Humans; Photoreceptor Cells; Proteasome Endopeptidase Complex; Retina; Ubiquitin
PubMed: 32274763
DOI: 10.1007/978-3-030-38266-7_13 -
Molecular Vision 2021To describe the derivation of photoreceptor precursor cells from human embryonic stem cells by coculture with RPE cells.
PURPOSE
To describe the derivation of photoreceptor precursor cells from human embryonic stem cells by coculture with RPE cells.
METHODS
Human embryonic stem cells were induced to differentiate into neural precursor cells and then cocultured with RPE cells to obtain cells showing retinal photoreceptor features. Immunofluorescent staining, reverse transcription-PCR (RT-PCR), and microarray analysis were performed to identify photoreceptor markers, and a cGMP assay was used for in vitro functional analysis. After subretinal injection in rat animal models, retinal function was determined with electroretinography and optokinetic response detection, and immunofluorescent staining was performed to assess the survival of the injected cells.
RESULTS
Cocultured cells were positive for rhodopsin, red and blue opsin, recoverin, and phosphodiesterase 6 beta on immunofluorescent staining and RT-PCR. Serial detection of stem cell-, neural precursor-, and photoreceptor-specific markers was noted in each stage of differentiation with microarray analysis. Increased cGMP hydrolysis in light-exposed conditions compared to that in dark conditions was observed. After the subretinal injection in the rats, preservation of optokinetic responses was noted up to 20 weeks, while electroretinographic response decreased. Survival of the injected cells was confirmed with positive immunofluorescence staining of human markers at 8 weeks.
CONCLUSIONS
Cells showed photoreceptor-specific features when stem cell-derived neurogenic precursors were cocultured with RPE cells.
Topics: Biomarkers; Cell Differentiation; Coculture Techniques; Electroretinography; Eye Proteins; Human Embryonic Stem Cells; Humans; Nystagmus, Optokinetic; Photoreceptor Cells; Real-Time Polymerase Chain Reaction; Retinal Pigment Epithelium; Stem Cells
PubMed: 34012231
DOI: No ID Found -
Cell Death & Disease Mar 2023Retinal detachment (RD) occurs in several major retinal conditions and often causes irreversible vision loss due to photoreceptor cell death. Retinal residential...
Retinal detachment (RD) occurs in several major retinal conditions and often causes irreversible vision loss due to photoreceptor cell death. Retinal residential microglial cells are activated following RD and participate in photoreceptor cell death via direct phagocytosis and the regulation of inflammatory responses. Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor exclusively expressed on microglial cells in the retina, and has been reported to affect microglial cell homeostasis, phagocytosis and inflammatory responses in the brain. In this study, increased expression of multiple cytokines and chemokines in the neural retina was observed starting at 3 h following RD. Trem2 knockout (Trem2) mice exhibited significantly more photoreceptor cell death than wild-type controls at 3 days after RD, and the number of TUNEL positive photoreceptor cells progressively decreased from day 3 to day 7 post-RD. A significant thinning of the outer nuclear layer (ONL), with multiple folds was observed in the Trem2 mice at 3 days post-RD. Trem2 deficiency reduced microglial cell infiltration and phagocytosis of stressed photoreceptors. There were more neutrophils in Trem2 retina following RD than in controls. Using purified microglial cells, we found Trem2 knockout is associated with increased CXCL12 expression. The aggravated photoreceptor cell death was largely reversed by blocking the CXCL12-CXCR4 mediated chemotaxis in Trem2 mice after RD. Our findings suggested that retinal microglia are protective in preventing further photoreceptor cell death following RD by phagocytosing presumably stressed photoreceptor cells and by regulating inflammatory responses. TREM2 is largely responsible for such protective effect and CXCL12 plays an important role in regulating neutrophil infiltration after RD. Collectively, our study pinpointed TREM2 as a potential target of microglial cells to ameliorate RD-induced photoreceptor cell death.
Topics: Mice; Animals; Microglia; Retinal Detachment; Apoptosis; Cell Death; Photoreceptor Cells; Photoreceptor Cells, Vertebrate; Membrane Glycoproteins; Receptors, Immunologic
PubMed: 36977680
DOI: 10.1038/s41419-023-05735-x -
Progress in Retinal and Eye Research Jan 2023Retinal gene supplementation therapy such as the first approved one, voretigene neparvovec, delivers a functioning copy of the missing gene enabling the protein... (Review)
Review
Retinal gene supplementation therapy such as the first approved one, voretigene neparvovec, delivers a functioning copy of the missing gene enabling the protein transcription in retinal cells and restore visual functions. After gene supplementation for the genetic defect, a complex network of functional regeneration is the consequence, whereas the extent is very individualized. Diagnostic and functional testings that have been used routinely by ophthalmologists so far to define the correct diagnosis, cannot be applied in the new context of defining small, sometimes subtle changes in visual functions. New view on retinal diagnostics is needed to understand this processes that define safety and efficacy of the treatment. Not only does vision have many aspects that must be addressed by specific evaluations and imaging techniques, but objective readouts of local retinal function for rods and cones separately have been an unmet need until recently. A reliable test-retest variability is necessary in rare diseases such as inherited retinal dystrophies, because statistics are often not applicable due to a low number of participants. Methods for a reliable individual evaluation of the therapy success are needed. In this manuscript we present an elaboration on retinal diagnostics combining psychophysics (eg. full-field stimulus threshold or dark adapted perimetry) as well as objective measures for local retinal function (eg. photopic and scotopic chromatic pupil campimetry) and retinal imaging for a meaningful workflow to apply in evaluation of the individual success in patients receiving gene therapy for photoreceptor diseases.
Topics: Humans; Vision, Ocular; Retinal Rod Photoreceptor Cells; Retinal Dystrophies; Visual Field Tests; Retinal Cone Photoreceptor Cells
PubMed: 36096933
DOI: 10.1016/j.preteyeres.2022.101115 -
Current Drug Targets 2020Photoreceptor loss is a major cause of blindness around the world. Stem cell therapy offers a new strategy in retina degenerative disease. Retinal progenitors can be... (Review)
Review
Photoreceptor loss is a major cause of blindness around the world. Stem cell therapy offers a new strategy in retina degenerative disease. Retinal progenitors can be derived from embryonic stem cells (ESC) in vitro, but cannot be processed to a mature state. In addition, the adult recipient retina presents a very different environment than the photoreceptor precursor donor. It seems that modulation of the recipient environment by ectopic development regulated growth factors for transplanted cells could generate efficient putative photoreceptors. The purpose of this review article was to investigate the signaling pathway of growth factors including: insulin-like growth factors (IGFs), fibroblast growth factors (FGF), Nerve growth factor (NGF), Brain-derived neurotrophic factor (BDNF), Taurin and Retinoic acid (RA) involved in the differentiation of neuroretina cell, like; photoreceptor and retinal progenitor cells. Given the results available in the related literature, the differentiation efficacy of ESCs toward the photoreceptor and retinal neurons and the important role of growth factors in activating signaling pathways such as Akt, Ras/Raf1/ and ERKs also inhibit the ASK1/JNK apoptosis pathway. Manipulating differentiated culture, growth factors can influence photoreceptor transplantation efficiency in retinal degenerative disease.
Topics: Animals; Cell Differentiation; Humans; Intercellular Signaling Peptides and Proteins; Photoreceptor Cells; Regeneration; Retina; Stem Cells; Vision Disorders
PubMed: 31755378
DOI: 10.2174/1389450120666191121103831 -
The Journal of Comparative Neurology Jun 2020MicroRNAs (MiRNAs) play important roles in posttranscriptional processes to regulate gene expression. MiRNAs control various biological processes, such as growth,... (Review)
Review
MicroRNAs (MiRNAs) play important roles in posttranscriptional processes to regulate gene expression. MiRNAs control various biological processes, such as growth, development, and differentiation. The continuous physiological function of photoreceptors and retinal pigment epithelium requires precise regulation to maintain their homeostasis and function; hence, these cells are highly susceptible to premature death in retinal degenerative disorders. MiRNAs are essential for the retinal cell maturation and function; the miR-183 cluster represents one of the most important regulatory factors for the photoreceptor cells. Various studies together with bioinformatics analyses have shown that many genes contributing to the differentiation pathway of photoreceptors are targets of the miR-183 cluster, and the miR-183 cluster dysregulation causes certain defects in the differentiation of the photoreceptors and other retinal neurons by influencing the expression of target genes. Misexpression of miR-183 cluster in the human retinal epithelial cells leads to the reprogramming and transformation of these cells to neuron- and photoreceptor-like cells, which are associated with the expression of neuron- and photoreceptor-specific markers in human retinal pigment epitheliums cells. The knockout of this cluster causes the destruction of the outer segment of the photoreceptors, which subsequently causes the cells to exhibit severe susceptibility to light and eventually degenerate. Hundreds of target genes in this family are likely to affect the development and maintenance of the retina. Identifying the genes that are regulated by the miRNA-183 cluster provides researchers with important insights into the complex development and regeneration mechanism of the retina and may offer a new way for maintaining and regenerating photoreceptor cells in neurodegenerative diseases.
Topics: Animals; Cell Differentiation; Cell Survival; Gene Expression Regulation; Humans; MicroRNAs; Photoreceptor Cells, Vertebrate
PubMed: 31785157
DOI: 10.1002/cne.24833 -
The Journal of Experimental Biology Apr 2022Retinal bipolar cells receive direct input from rod and cone photoreceptors and send axons into the inner retina, synapsing onto amacrine and ganglion cells. Bipolar...
Retinal bipolar cells receive direct input from rod and cone photoreceptors and send axons into the inner retina, synapsing onto amacrine and ganglion cells. Bipolar cell responses can be either depolarizing (ON) or hyperpolarizing (OFF); in lower vertebrates, bipolar cells receive mixed rod and cone input, whereas in mammals, input is mostly segregated into 14 classes of cone ON and OFF cells and a single rod ON bipolar cell. We show that lamprey, like mammals, have rod bipolar cells with little or no cone input, but these cells are OFF rather than ON. They have a characteristic morphology and a spectral sensitivity nearly indistinguishable from that of rod photoreceptors. In background light known to saturate rods, rod bipolar cells are also saturated and cannot respond to increment flashes. Our results suggest that early vertebrate progenitors of both agnathans and gnathostomes may have had a more fluid retinal organization than previously thought.
Topics: Animals; Mammals; Petromyzon; Retina; Retinal Bipolar Cells; Retinal Cone Photoreceptor Cells; Retinal Rod Photoreceptor Cells; Vertebrates
PubMed: 35319772
DOI: 10.1242/jeb.243949 -
Scientific Reports May 2022NR2E3 is an orphan nuclear receptor whose loss-of-function causes abnormal retinal photoreceptor development and degeneration. However, despite that many nuclear...
NR2E3 is an orphan nuclear receptor whose loss-of-function causes abnormal retinal photoreceptor development and degeneration. However, despite that many nuclear receptors are regulated by binding of small molecule ligands, biological small molecule ligands regulating NR2E3 have not been identified. Identification of an endogenous NR2E3 ligand might reveal a previously unrecognized component contributing to retinal development and maintenance. Here we report that biliverdin, a conserved green pigment from heme catabolism, regulates NR2E3 and is necessary for zebrafish retinal photoreceptor development. Biliverdin from retinal extracts specifically bound to NR2E3's ligand-binding domain and induced NR2E3-dependent reporter gene expression. Inhibition of biliverdin synthesis decreased photoreceptor cell populations in zebrafish larvae, and this phenotype was alleviated by exogenously supplied biliverdin. Thus, biliverdin is an endogenous small molecule ligand for NR2E3 and a component necessary for the proper development of photoreceptor cells. This result suggests a possible role of heme metabolism in the regulation of retinal photoreceptor cell development.
Topics: Animals; Biliverdine; Heme; Ligands; Orphan Nuclear Receptors; Photoreceptor Cells; Photoreceptor Cells, Vertebrate; Receptors, Cytoplasmic and Nuclear; Retinal Degeneration; Zebrafish; Zebrafish Proteins
PubMed: 35508617
DOI: 10.1038/s41598-022-11502-3 -
Philosophical Transactions of the Royal... Jan 2016Vision allows animals to detect spatial differences in environmental light levels. High-resolution image-forming eyes evolved from low-resolution eyes via increases in... (Review)
Review
Vision allows animals to detect spatial differences in environmental light levels. High-resolution image-forming eyes evolved from low-resolution eyes via increases in photoreceptor cell number, improvements in optics and changes in the neural circuits that process spatially resolved photoreceptor input. However, the evolutionary origins of the first low-resolution visual systems have been unclear. We propose that the lowest resolving (two-pixel) visual systems could initially have functioned in visual phototaxis. During visual phototaxis, such elementary visual systems compare light on either side of the body to regulate phototactic turns. Another, even simpler and non-visual strategy is characteristic of helical phototaxis, mediated by sensory-motor eyespots. The recent mapping of the complete neural circuitry (connectome) of an elementary visual system in the larva of the annelid Platynereis dumerilii sheds new light on the possible paths from non-visual to visual phototaxis and to image-forming vision. We outline an evolutionary scenario focusing on the neuronal circuitry to account for these transitions. We also present a comprehensive review of the structure of phototactic eyes in invertebrate larvae and assign them to the non-visual and visual categories. We propose that non-visual systems may have preceded visual phototactic systems in evolution that in turn may have repeatedly served as intermediates during the evolution of image-forming eyes.
Topics: Animals; Biological Evolution; Eye; Gene Expression Regulation; Opsins; Photoreceptor Cells
PubMed: 26598725
DOI: 10.1098/rstb.2015.0042 -
Journal of Neurogenetics Dec 2017Sight depends on the intimate association between photoreceptors and pigment epithelial cells. The evolutionary origin of this cellular tandem can be traced back to the... (Review)
Review
Sight depends on the intimate association between photoreceptors and pigment epithelial cells. The evolutionary origin of this cellular tandem can be traced back to the emergence of bilateral animals, at least 450 million years ago, as they define the minimal unit of the ancestral prototypic eye. Phototransduction is a demanding process from the energetic and homeostatic points of view, and not surprisingly photoreceptive cells are particularly susceptible to damage and degeneration. Here, we will examine the different ancillary roles that the pigmented cells play in the physiology and homeostasis of photoreceptors, linking each one of these processes to the most common hereditary retinal diseases. We will discuss the challenges and opportunities of recent therapeutic advances based on cell and gene replacement. The transition from animal models to clinical trials will be addressed for each one of the different therapeutic strategies with a special focus on those depending on retinal-pigmented epithelial cells. Finally, we will discuss the potential impact of combining CRISPR technologies with gene and cell therapy approaches, which - in the frame of the personalized medicine revolution - may constitute a leap forward in the treatment of retinal dystrophies.
Topics: Animals; Genetic Therapy; Photoreceptor Cells; Retinal Degeneration; Retinal Pigment Epithelium
PubMed: 29113536
DOI: 10.1080/01677063.2017.1395876