Retinal neurons establish mosaic patterning by excluding homotypic somata from their dendritic territories.

In vertebrate retina, individual neurons of the same type are distributed regularly across the tissue in a pattern known as a mosaic. Establishment of mosaics during development requires cell-cell repulsion among homotypic neurons, but the mechanisms underlying this repulsion remain unknown. Here, we show that two mouse retinal cell types, OFF and ON starburst amacrine cells, establish mosaic spacing by using their dendritic arbors to repel neighboring homotypic somata. Using transgenic tools and single-cell labeling, we identify a developmental period when starburst somata are contacted by neighboring starburst dendrites; these serve to exclude somata from settling within the neighbor's dendritic territory. Dendrite-soma exclusion is mediated by MEGF10, a cell-surface molecule required for starburst mosaic patterning. Our results implicate dendrite-soma exclusion as a key mechanism underlying starburst mosaic spacing and raise the possibility that this could be a general mechanism for mosaic patterning across many cell types and species.

Mycb and Mych stimulate Müller glial cell reprogramming and proliferation in the uninjured and injured zebrafish retina.

In the injured zebrafish retina, Müller glial cells (MG) reprogram to adopt retinal stem cell properties and regenerate damaged neurons. The strongest zebrafish reprogramming factors might be good candidates for stimulating a similar regenerative response by mammalian MG. Myc proteins are potent reprogramming factors that can stimulate cellular plasticity in differentiated cells; however, their role in MG reprogramming and retina regeneration remains poorly explored. Here, we report that retinal injury stimulates mycb and mych expression and that, although both Mycb and Mych stimulate MG reprogramming and proliferation, only Mych enhances retinal neuron apoptosis. RNA-sequencing analysis of wild-type, mychmut and mycbmut fish revealed that Mycb and Mych regulate ∼40% and ∼16%, respectively, of the genes contributing to the regeneration-associated transcriptome of MG. Of these genes, those that are induced are biased towards regulation of ribosome biogenesis, protein synthesis, DNA synthesis, and cell division, which are the top cellular processes affected by retinal injury, suggesting that Mycb and Mych are potent MG reprogramming factors. Consistent with this, forced expression of either of these proteins is sufficient to stimulate MG proliferation in the uninjured retina.

The Variety of Mechanosensitive Ion Channels in Retinal Neurons.

Alterations in intraocular and external pressure critically involve the pathogenesis of glaucoma, traumatic retinal injury (TRI), and other retinal disorders, and retinal neurons have been reported to express multiple mechanical-sensitive channels (MSCs) in recent decades. However, the role of MSCs in visual functions and pressure-related retinal conditions has been unclear. This review will focus on the variety and functional significance of the MSCs permeable to K+, Na+, and Ca2+, primarily including the big potassium channel (BK); the two-pore domain potassium channels TRAAK and TREK; Piezo; the epithelial sodium channel (ENaC); and the transient receptor potential channels vanilloid TRPV1, TRPV2, and TRPV4 in retinal photoreceptors, bipolar cells, horizontal cells, amacrine cells, and ganglion cells. Most MSCs do not directly mediate visual signals in vertebrate retinas. On the other hand, some studies have shown that MSCs can open in physiological conditions and regulate the activities of retinal neurons. While these data reasonably predict the crossing of visual and mechanical signals, how retinal light pathways deal with endogenous and exogenous mechanical stimulation is uncertain.

A Novel Cre Recombinase Mouse Strain for Cell-Specific Deletion of Floxed Genes in Ribbon Synapse-Forming Retinal Neurons.

We generated a novel Cre mouse strain for cell-specific deletion of floxed genes in ribbon synapse-forming retinal neurons. Previous studies have shown that the RIBEYE promotor targets the expression of recombinant proteins such as fluorescently tagged RIBEYE to photoreceptors and retinal bipolar cells and generates fluorescent synaptic ribbons in situ in these neurons. Here, we used the same promotor to generate a novel transgenic mouse strain in which the RIBEYE promotor controls the expression of a Cre-ER(T2) recombinase (RIBEYE-Cre). To visualize Cre expression, the RIBEYE-Cre animals were crossed with ROSA26 tau-GFP (R26-τGFP) reporter mice. In the resulting RIBEYE-Cre/R26 τGFP animals, Cre-mediated removal of a transcriptional STOP cassette results in the expression of green fluorescent tau protein (tau-GFP) that binds to cellular microtubules. We detected robust tau-GFP expression in retinal bipolar cells. Surprisingly, we did not find fluorescent tau-GFP expression in mouse photoreceptors. The lack of tau-GFP reporter protein in these cells could be based on the previously reported absence of tau protein in mouse photoreceptors which could lead to the degradation of the recombinant tau protein. Consistent with this, we detected Cre and tau-GFP mRNA in mouse photoreceptor slices by RT-PCR. The transgenic RIBEYE-Cre mouse strain provides a new tool to study the deletion of floxed genes in ribbon synapse-forming neurons of the retina and will also allow for analyzing gene deletions that are lethal if globally deleted in neurons.

MicroRNA-193a Promotes Apoptosis in Retinal Neuronal Cells in Early-Stage Diabetic (DM) Rat via Wilms' Tumor Gene 1.

OBJECTIVE: This study aimed to investigate the role and mechanism of microRNA (miR)-193a in promoting apoptosis of retinal neuronal cells in early diabetic (DM) rats. METHODS: Seventy-two male SD-grade rats were selected to establish a DM model by intraperitoneal injection of streptozotocin (STZ), and randomly divided into a control group (blank control group), a DM group (diabetic model group), a DM+miR-NC inhibitor group (miR-193a inhibition negative control group), a DM+miR-193a inhibitor group (miR-193a inhibitor group), DM+miR-NC mimic group (miR-193a overexpression negative control group), DM+miR-193a mimic group (miR-193a overexpression group), with12 rats in each group. RESULTS: The miR-193a expression, apoptosis rate, and Bax, Caspase3, and Caspase9 protein expression levels were elevated, and Bcl-2 protein expression was decreased in the retinal tissues of DM rats and high glucose-induced rat retinal neuronal cells, while miR-193a inhibitors reversed these processes. These dual luciferase reporter assay showed that WT1CDS, and WT1Mut were lower in the miR-193a group than in the miR-NC group (P<0.05); WT1 protein expression was reduced in the retinal tissues of DM rat and high glucose-induced rat retinal neuronal cells, and miR-193a inhibitors increased WT1 protein expression. Compared with cells co-transfected with miR-193a and WT1vector, miR-193a and WT1 cotransfection inhibited high glucose-induced apoptosis in retinal neuronal cells and regulated apoptotic protein expression. miR-193a was highly expressed and WT1 was lowly expressed in retinal tissues of DM rats and high glucose-induced rat retinal neuronal cells. CONCLUSION: miR-193a could inhibit early retinal neuronal cell apoptosis in DM rats by targeting and negatively regulating WT1 expression.

Coexistence within one cell of microvillous and ciliary phototransductions across M1- through M6-IpRGCs.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) serve as primary photoceptors by expressing the photopigment, melanopsin, and also as retinal relay neurons for rod and cone signals en route to the brain, in both cases for the purpose of non-image vision as well as aspects of image vision. So far, six subtypes of ipRGCs (M1 through M6) have been characterized. Regarding their phototransduction mechanisms, we have previously found that, unconventionally, rhabdomeric (microvillous) and ciliary signaling motifs co-exist within a given M1-, M2-, and M4-ipRGC, with the first mechanism involving PLCß4 and TRPC6,7 channels and the second involving cAMP and HCN channels. We have now examined M3-, M5-, and M6-cells and found that each cell likewise uses both signaling pathways for phototransduction, despite differences in the percentage representation by each pathway in a given ipRGC subtype for bright-flash responses (and saturated except for M6-cells). Generally, M3- and M5-cells show responses quite similar in kinetics to M2-responses, and M6-cell responses resemble broadly those of M1-cells although much lower in absolute sensitivity and amplitude. Therefore, similar to rod and cone subtypes in image vision, ipRGC subtypes possess the same phototransduction mechanism(s) even though they do not show microvilli or cilia morphologically.

Potential involvement of miR-183/96/182 cluster-gene target interactions in transdifferentiation of human retinal pigment epithelial cells into retinal neurons.

miR-183/96/182 cluster plays a critical role in the developing retina by regulating many target genes involved in signaling pathways. This study aimed to survey the miR-183/96/182 cluster-target interactions that, potentially contribute to human retinal pigmented epithelial (hRPE) cell differentiation into photoreceptors. Target genes of the miR-183/96/182 cluster were obtained from miRNA-target databases and applied to construct miRNA-target networks. Gene ontology and KEGG pathway analysis was performed. miR-183/96/182 cluster sequence was cloned into an eGFP-intron splicing cassette in an AAV2 vector and overexpressed in hRPE cells. The expression level of target genes including HES1, PAX6, SOX2, CCNJ, and RORΒ was evaluated using qPCR. Our results showed that miR-183, miR-96, and miR-182 share 136 target genes that are involved in cell proliferation pathways such as PI3K/AKT and MAPK pathway. qPCR data indicated a 22-, 7-, and 4-fold overexpression of miR-183, miR-96, and miR-182, respectively, in infected hRPE cells. Consequently, the downregulation of several key targets such as PAX6, CCND2, CDK5R1, and CCNJ and upregulation of a few retina-specific neural markers such as Rhodopsin, red opsin, and CRX was detected. Our findings suggest that the miR-183/96/182 cluster may induce hRPE transdifferentiation by targeting key genes that involve in the cell cycle and proliferation pathways.

Translocator protein 18 kDa regulates retinal neuron apoptosis and pyroptosis in glaucoma.

Glaucoma is the leading cause of blindness worldwide. However, our insufficient understanding of the pathogenesis of glaucoma has limited the development of effective treatments. Because recent research has highlighted the importance of non-coding RNAs (ncRNAs) in various diseases, we investigated their roles in glaucoma. Specifically, we detected expression changes of ncRNAs in cell and animal models of acute glaucoma. Further analysis revealed that the Ier2/miR-1839/TSPO axis was critical to cell loss and retinal damage. The knockdown of Ier2, the overexpression of miR-1839, and the silencing of TSPO effectively prevented retinal damage and cell loss. Furthermore, we found that the Ier2/miR-1839/TSPO axis regulated the pyroptosis and apoptosis of retinal neurons through the NLRP3/caspase1/GSDMD, cleaved-caspase3 pathways. In addition to high expression in the retina, TSPO expression was found to be significantly higher in the dorsal lateral geniculate nucleus (DLG) of the brain in the pathologically high intraocular pressure (ph-IOP) rat model, as well as in the peripheral blood mononuclear cells (PBMCs) of glaucoma patients with high IOP. These results indicate that TSPO, which is regulated by Ier2/miR-1839, plays an important role in the pathogenesis of glaucoma, and this study provides a theoretical basis and a new target for the diagnosis and treatment of glaucoma.

Role of CAST-Drp1 Pathway in Retinal Neuron-Regulated Necrosis in Experimental Glaucoma.

OBJECTIVE: Numerous studies have indicated that excitatory amino acid toxicity, such as glutamate toxicity, is involved in glaucoma. In addition, excessive glutamate can lead to an intracellular calcium overload, resulting in regulated necrosis. Our previous studies have found that the calpastatin (CAST)-calpain pathway plays an important role in retinal neuron-regulated necrosis after glutamate injury. Although inhibition of the calpain pathway can decrease regulated necrosis, necrotic cells remain. It has been suggested that there are other molecules that participate in retinal neuron-regulated necrosis. CAST is an important regulator of dynamin-related protein 1 (Drp1)-mediated mitochondrial defects. Thus, the aim of this study was to determine whether the CAST-Drp1 pathway may be an underlying signaling axis in neuron-regulated necrosis. METHODS: Using cultured retinal neurons and in an in-vivo glaucoma model induced by glutamate overload, members of the CAST-Drp1 pathway were assessed by immunofluorescence, Western blotting, Phos-tagTM SDS-PAGE, and co-immunoprecipitation assays. Moreover, the black and white box test was performed on the rats. RESULTS: We found that more retinal neuron-regulated necrosis and Drp1 activation as well as lower CAST levels were present in the glutamate-induced glaucoma model. Rats with glutamate-induced glaucoma exhibited impaired visual function. We also observed retinal neuron-regulated necrosis and Drp1 activity decreased, and impaired vision recovered after CAST active peptide application, indicating that the CAST-Drp1 pathway plays a critical role in retinal neuron-regulated necrosis and visual function. CONCLUSION: The results of this study indicate that the CAST-Drp1 pathway protects against retinal neuron-regulated necrosis, which may expand the therapeutic targets for the treatment of neurodegenerative disorders involving dysfunction of glutamate metabolism, such as glaucoma.

Cell Sources for Retinal Regeneration: Implication for Data Translation in Biomedicine of the Eye.

The main degenerative diseases of the retina include macular degeneration, proliferative vitreoretinopathy, retinitis pigmentosa, and glaucoma. Novel approaches for treating retinal diseases are based on cell replacement therapy using a variety of exogenous stem cells. An alternative and complementary approach is the potential use of retinal regeneration cell sources (RRCSs) containing retinal pigment epithelium, ciliary body, Müller glia, and retinal ciliary region. RRCSs in lower vertebrates in vivo and in mammals mostly in vitro are able to proliferate and exhibit gene expression and epigenetic characteristics typical for neural/retinal cell progenitors. Here, we review research on the factors controlling the RRCSs' properties, such as the cell microenvironment, growth factors, cytokines, hormones, etc., that determine the regenerative responses and alterations underlying the RRCS-associated pathologies. We also discuss how the current data on molecular features and regulatory mechanisms of RRCSs could be translated in retinal biomedicine with a special focus on (1) attempts to obtain retinal neurons de novo both in vivo and in vitro to replace damaged retinal cells; and (2) investigations of the key molecular networks stimulating regenerative responses and preventing RRCS-related pathologies.

Brca1 Is Regulated by the Transcription Factor Gata3, and Its Silencing Promotes Neural Differentiation in Retinal Neurons.

Previous studies have indicated that Brca1 (Breast cancer suppressor gene 1) plays an important role in neural development and degenerative diseases. However, the bioactivity and regulatory mechanism of Brca1 expression in retinal neurocytes remain unclear. In the present study, our data indicated that Brca1 maintains the state of neuronal precursor cells. Brca1 silencing induces differentiation in 661W cells. Nestin, a marker of precursor cells, was significantly decreased in parallel with Brca1 silencing in 661W cells, whereas Map2 (Microtubule associated protein 2), a marker of differentiated neurons, was significantly increased. Neurite outgrowth was increased by ~4.0-fold in Brca1-silenced cells. Moreover, DNA affinity purification assays and ChIP assays demonstrated that Gata3 (GATA binding protein 3) regulates Brca1 transcription in 661W cells. Silencing or overexpressing Gata3 could significantly regulate the expression of Brca1 and affect its promoter inducibility. Furthermore, the expression of Gata3 generally occurred in parallel with that of Brca1 in developing mouse retinas. Both Gata3 and Brca1 are expressed in the neonatal mouse retina but are developmentally silenced with age. Exogenous Gata3 significantly inhibited neural activity by decreasing synaptophysin and neurite outgrowth. Thus, this study demonstrated that Brca1 is transcriptionally regulated by Gata3. Brca1/Gata3 silencing is involved in neuronal differentiation and maturation.

Dephosphorylation of ERK1/2 and DRP1 S585 regulates mitochondrial dynamics in glutamate toxicity of retinal neurons in vitro.

There are many theories surrounding the pathogenesis of glaucoma, and glutamate excitatory toxicity has been suggested to play an important role. Some studies have shown that glutamate excitatory toxicity is associated with mitochondrial dynamics; however, the relationship between glutamate excitatory toxicity and mitochondrial dynamics in the pathogenesis of glaucoma remains unclear. In this study, the glutamate transporter inhibitor, threohydroxyaspartate, was used to simulate the glutamate excitatory toxicity cell model of rat retinal neurons in vitro, and the changes in the level of proteins related to mitochondrial dynamics, mitochondrial morphology, and length of neuronal axons were measured. We found that in the glutamate excitotoxicity model, retinal neurons can promote mitochondrial fusion by reducing the phosphorylation of ERK1/2 and its downstream protein DRP1 S585, and enhance its ability to resist the excitotoxicity of glutamate. At the same time, the DRP1-specific inhibitor, Mdivi-1, could promote the mitochondrial fusion of retinal neurons.

Iris-derived induced pluripotent stem cells that express GFP in all somatic cells of mice and differentiate into functional retinal neurons.

When regenerated tissue is generated from induced pluripotent stem cells (iPSCs), it is necessary to track and identify the transplanted cells. Fluorescently-labeled iPSCs synthesize a fluorescent substance that is easily tracked. However, the expressed protein should not affect the original genome sequence or pluripotency. To solve this problem, we created a cell tool for basic research on iPSCs. Iris tissue-derived cells from GFP fluorescence-expressing mice (GFP-DBA/2 mice) were reprogrammed to generate GFP mouse iris-derived iPSCs (M-iris GFP iPSCs). M-iris GFP iPSCs expressed cell markers characteristic of iPSCs and showed pluripotency in differentiating into the three germ layers. In addition, when expressing GFP, the cells differentiated into functional recoverin- and calbindin-positive cells. Thus, this cell line will facilitate future studies on iPSCs.

Differential Susceptibility of Retinal Neurons to the Loss of Mitochondrial Biogenesis Factor Nrf1.

The retina, the accessible part of the central nervous system, has served as a model system to study the relationship between energy utilization and metabolite supply. When the metabolite supply cannot match the energy demand, retinal neurons are at risk of death. As the powerhouse of eukaryotic cells, mitochondria play a pivotal role in generating ATP, produce precursors for macromolecules, maintain the redox homeostasis, and function as waste management centers for various types of metabolic intermediates. Mitochondrial dysfunction has been implicated in the pathologies of a number of degenerative retinal diseases. It is well known that photoreceptors are particularly vulnerable to mutations affecting mitochondrial function due to their high energy demand and susceptibility to oxidative stress. However, it is unclear how defective mitochondria affect other retinal neurons. Nuclear respiratory factor 1 (Nrf1) is the major transcriptional regulator of mitochondrial biogenesis, and loss of Nrf1 leads to defective mitochondria biogenesis and eventually cell death. Here, we investigated how different retinal neurons respond to the loss of Nrf1. We provide in vivo evidence that the disruption of Nrf1-mediated mitochondrial biogenesis results in a slow, progressive degeneration of all retinal cell types examined, although they present different sensitivity to the deletion of Nrf1, which implicates differential energy demand and utilization, as well as tolerance to mitochondria defects in different neuronal cells. Furthermore, transcriptome analysis on rod-specific Nrf1 deletion uncovered a previously unknown role of Nrf1 in maintaining genome stability.

Intrinsic Expression of Coagulation Factors and Protease Activated Receptor 1 (PAR1) in Photoreceptors and Inner Retinal Layers.

The aim of this study was to characterize the distribution of the thrombin receptor, protease activated receptor 1 (PAR1), in the neuroretina. Neuroretina samples of wild-type C57BL/6J and PAR1-/- mice were processed for indirect immunofluorescence and Western blot analysis. Reverse transcription quantitative real-time PCR (RT-qPCR) was used to determine mRNA expression of coagulation Factor X (FX), prothrombin (PT), and PAR1 in the isolated neuroretina. Thrombin activity following KCl depolarization was assessed in mouse neuroretinas ex vivo. PAR1 staining was observed in the retinal ganglion cells, inner nuclear layer cells, and photoreceptors in mouse retinal cross sections by indirect immunofluorescence. PAR1 co-localized with rhodopsin in rod outer segments but was not expressed in cone outer segments. Western blot analysis confirmed PAR1 expression in the neuroretina. Factor X, prothrombin, and PAR1 mRNA expression was detected in isolated neuroretinas. Thrombin activity was elevated by nearly four-fold in mouse neuroretinas following KCl depolarization (0.012 vs. 0.044 mu/mL, p = 0.0497). The intrinsic expression of coagulation factors in the isolated neuroretina together with a functional increase in thrombin activity following KCl depolarization may suggest a role for the PAR1/thrombin pathway in retinal function.

Gene regulatory networks controlling temporal patterning, neurogenesis, and cell-fate specification in mammalian retina.

Gene regulatory networks (GRNs), consisting of transcription factors and their target sites, control neurogenesis and cell-fate specification in the developing central nervous system. In this study, we use integrated single-cell RNA and single-cell ATAC sequencing (scATAC-seq) analysis in developing mouse and human retina to identify multiple interconnected, evolutionarily conserved GRNs composed of cell-type-specific transcription factors that both activate genes within their own network and inhibit genes in other networks. These GRNs control temporal patterning in primary progenitors, regulate transition from primary to neurogenic progenitors, and drive specification of each major retinal cell type. We confirm that NFI transcription factors selectively activate expression of genes promoting late-stage temporal identity in primary retinal progenitors and identify other transcription factors that regulate rod photoreceptor specification in postnatal retina. This study inventories cis- and trans-acting factors that control retinal development and can guide cell-based therapies aimed at replacing retinal neurons lost to disease.

Targeted deletion of PAC1 receptors in retinal neurons enhances neuron loss and axonopathy in a model of multiple sclerosis and optic neuritis.

Chronic inflammation drives synaptic loss in multiple sclerosis (MS) and is also commonly observed in other neurodegenerative diseases. Clinically approved treatments for MS provide symptomatic relief but fail to halt neurodegeneration and neurological decline. Studies in animal disease models have demonstrated that the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1) exhibits anti-inflammatory, neuroprotective and regenerative properties. Anti-inflammatory actions appear to be mediated primarily by two receptors, VPAC1 and VPAC2, which also bind vasoactive intestinal peptide (VIP). Pharmacological experiments indicate that another receptor, PAC1 (ADCYAP1R1), which is highly selective for PACAP, provides protection to neurons, although genetic evidence and other mechanistic information is lacking. To determine if PAC1 receptors protect neurons in a cell-autonomous manner, we used adeno-associated virus (AAV2) to deliver Cre recombinase to the retina of mice harboring floxed PAC1 alleles. Mice were then subjected to chronic experimental autoimmune encephalomyelitis (EAE), a disease model that recapitulates major clinical and pathological features of MS and associated optic neuritis. Unexpectedly, deletion of PAC1 in naïve mice resulted in a deficit of retinal ganglionic neurons (RGNs) and their dendrites, suggesting a homeostatic role of PAC1. Moreover, deletion of PAC1 resulted in increased EAE-induced loss of a subpopulation of RGNs purported to be vulnerable in animal models of glaucoma. Increased axonal pathology and increased secondary presence of microglia/macrophages was also prominently seen in the optic nerve. These findings demonstrate that neuronal PAC1 receptors play a homeostatic role in protecting RGNs and directly protects neurons and their axons against neuroinflammatory challenge. SIGNIFICANCE STATEMENT: Chronic inflammation is a major component of neurodegenerative diseases and plays a central role in multiple sclerosis (MS). Current treatments for MS do not prevent neurodegeneration and/or neurological decline. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to have anti-inflammatory, neuroprotective and regenerative properties but the cell type- and receptor-specific mechanisms are not clear. To test whether the protective effects of PACAP are direct on the PAC1 receptor subtype on neurons, we delete PAC1 receptors from neurons and investigate neuropathologigical changes in an animal model of MS. The findings demonstrate that PAC1 receptors on neurons play a homeostatic role in maintaining neuron health and can directly protect neurons and their axons during neuroinflammatory disease.

Retinal blood flow dysregulation precedes neural retinal dysfunction in type 2 diabetic mice.

We investigated and compared the susceptibility of retinal blood flow regulation and neural function in mice developing type 2 diabetes. The longitudinal changes in retinal neuronal function and blood flow responses to a 10-min systemic hyperoxia and a 3-min flicker stimulation were evaluated every 2 weeks in diabetic db/db mice and nondiabetic controls (db/m) from age 8 to 20 weeks. The retinal blood flow and neural activity were assessed using laser speckle flowgraphy and electroretinography (ERG), respectively. The db/db mice had significantly higher blood glucose levels and body weight. The resting retinal blood flow was steady and comparable between two groups throughout the study. Hyperoxia elicited a consistent decrease, and flicker light an increase, in retinal blood flow in db/m mice independent of age. However, these flow responses were significantly diminished in db/db mice at 8 weeks old and then the mice became unresponsive to stimulations at 12 weeks. Subsequently, the ERG implicit time for oscillatory potential was significantly increased at 14 weeks of age while the a-wave and b-wave amplitudes and implicit times remained unchanged. The deficiencies of flow regulation and neurovascular coupling in the retina appear to precede neural dysfunction in the mouse with type 2 diabetes.

Peripapillary retinal nerve fiber layer thickness in patients with unilateral retinal vein occlusion.

This study evaluated longitudinal changes in peripapillary retinal nerve fiber layer (pRNFL) thickness in eyes affected with branch and central retinal vein occlusion (BRVO and CRVO, respectively) and fellow eyes. This retrospective case-control study included patients with newly diagnosed unilateral BRVO (46 patients) or unilateral CRVO (27 patients). The control group included 48 patients without abnormal findings on the fundus examination. Global and all-sector pRNFL thicknesses were greater in eyes with BRVO and CRVO than in fellow eyes at baseline; however, at 24 months, this difference remained only in the temporal sector of eyes affected with CRVO. Although the global pRNFL thicknesses of the fellow eyes in the BRVO and CRVO groups decreased significantly at 24 months compared to baseline (p = 0.001 and p = 0.011, respectively), there was no significant difference in the normal control group (p = 0.824). The global, inferior temporal, and inferior nasal pRNFL thicknesses at 12 and 24 months were significantly lower in the fellow eyes of the CRVO group than in those of the BRVO and normal control groups. The fellow eyes of patients with BRVO and CRVO suffered a significant reduction in pRNFL thickness compared to normal controls, indicating that they are susceptible to pRNFL damage.

Retinal Stem Cell 'Retirement Plans': Growth, Regulation and Species Adaptations in the Retinal Ciliary Marginal Zone.

The vertebrate retina develops from a specified group of precursor cells that adopt distinct identities and generate lineages of either the neural retina, retinal pigmented epithelium, or ciliary body. In some species, including teleost fish and amphibians, proliferative cells with stem-cell-like properties capable of continuously supplying new retinal cells post-embryonically have been characterized and extensively studied. This region, termed the ciliary or circumferential marginal zone (CMZ), possibly represents a conserved retinal stem cell niche. In this review, we highlight the research characterizing similar CMZ-like regions, or stem-like cells located at the peripheral margin, across multiple different species. We discuss the proliferative parameters, multipotency and growth mechanisms of these cells to understand how they behave in vivo and how different molecular factors and signalling networks converge at the CMZ niche to regulate their activity. The evidence suggests that the mature retina may have a conserved propensity for homeostatic growth and plasticity and that dysfunction in the regulation of CMZ activity may partially account for dystrophic eye growth diseases such as myopia and hyperopia. A better understanding of the properties of CMZ cells will enable important insight into how an endogenous generative tissue compartment can adapt to altered retinal physiology and potentially even restore vision loss caused by retinal degenerative conditions.