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Long noncoding RNA (lncRNA) regulates the proliferation and migration of human retinal endothelial cells, as well as retinal neovascularization in diabetic retinopathy. Based on similarities between the pathogenesis of retinopathy of prematurity (ROP) and diabetic retinopathy, lncRNA may also play a role in ROP. Seven-day-old mice were administered 75 ± 2% oxygen for 5 days and normoxic air for another 5 days to establish a ROP model. Expression of lncRNA and mRNA in the retinal tissue of mice was detected by high-throughput sequencing technology, and biological functions of the resulted differentially expressed RNAs were evaluated by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. The results showed that compared with the control group, 57 lncRNAs were differentially expressed, including 43 upregulated and 14 downregulated, in the retinal tissue of ROP mice. Compared with control mice, 42 mRNAs were differentially expressed in the retinal tissue of ROP mice, including 24 upregulated and 18 downregulated mRNAs. Differentially expressed genes were involved in ocular development and related metabolic pathways. The differentially expressed lncRNAs may regulate ROP in mice via microRNAs and multiple signaling pathways. Our results revealed that these differentially expressed lncRNAs may be therapeutic targets for ROP treatment. This study was approved by the Medical Ethics Committee of Shengjing Hospital of China Medical University on February 25, 2016 (approval No. 2016PS074K).

Previously, we have shown that Onecut1 (Oc1) and Onecut2 (Oc2) are expressed in retinal progenitor cells, developing retinal ganglion cells (RGCs), and horizontal cells (HCs). However, in Oc1 -null mice, we only observed an 80% reduction in HCs, but no defects in other cell types. We postulated that the lack of defects in other cell types in Oc1 -null retinas was a result of redundancy with Oc2. To test this theory, we have generated Oc2 -null mice and now show that their retinas also only have defects in HCs, with a 50% reduction in their numbers. However, when both Oc1 and Oc2 are knocked out, the retinas exhibit more profound defects in the development of all early retinal cell types, including completely failed genesis of HCs, compromised generation of cones, reduced production (by 30%) of RGCs, and absence of starburst amacrine cells. Cone subtype diversification and RGC subtype composition also were affected in the double-null retina. Using RNA-Seq expression profiling, we have identified downstream genes of Oc1 and Oc2, which not only confirms the redundancy between the two factors and renders a molecular explanation for the defects in the double-null retinas, but also shows that the onecut factors suppress the production of the late cell type, rods, indicating that the two factors contribute to the competence of retinal progenitor cells for the early retinal cell fates. Our results provide insight into how onecut factors regulate the creation of cellular diversity in the retina and, by extension, in the central nervous system in general. Significance We show that the onecut transcription factors, Onecut1 and Onecut2, redundantly regulate the formation of all four early-born retinal cell types, namely horizontal cells, ganglion cells, cones, and amacrine cells, and prevent precocious formation of the late retinal cell type, rods. Expression profiling suggests these two factors regulate a shared set of downstream genes to maintain competence for the early retinal cell types and to regulate generation of various subtypes of retinal ganglion cells. This study lays the foundation for further examination of how onecut factors regulate cell differentiation in the retina, as well as in the central nervous system in general.

Despite mounting evidence that the mammalian retina is exceptionally reliant on proper NAD + homeostasis for health and function, the specific roles of subcellular NAD + pools in retinal development, maintenance, and disease remain obscure. Here, we show that deletion of the nuclear-localized NAD + synthase nicotinamide mononucleotide adenylyltransferase-1 (NMNAT1) in the developing murine retina causes early and severe degeneration of photoreceptors and select inner retinal neurons via multiple distinct cell death pathways. This severe phenotype is associated with disruptions to retinal central carbon metabolism, purine nucleotide synthesis, and amino acid pathways. Furthermore, transcriptomic and immunostaining approaches reveal dysregulation of a collection of photoreceptor and synapse-specific genes in NMNAT1 knockout retinas prior to detectable morphological or metabolic alterations. Collectively, our study reveals previously unrecognized complexity in NMNAT1-associated retinal degeneration and suggests a yet-undescribed role for NMNAT1 in gene regulation during photoreceptor terminal differentiation.

Age-related macular degeneration (AMD) leads to gradual central vision loss and is the third leading cause of irreversible blindness worldwide. The underlying mechanisms for this progressive neurodegenerative disease remain unclear and there is currently no preventive treatment for dry AMD. Sodium iodate (NaIO3) has been reported to induce AMD-like retinal pathology in mice. We established a mouse model for AMD to evaluate the effects of quercetin on NaIO3-induced retinal apoptosis, and to investigate the pertinent underlying mechanisms. Our in vitro results indicated that quercetin protected human retinal pigment epithelium (ARPE-19) cells from NaIO3-induced apoptosis by inhibiting reactive oxygen species production and loss of mitochondrial membrane potential as detected by Annexin V-FITC/PI flow cytometry. We also evaluated the relative expression of proteins in the apoptosis pathway. Quercetin downregulated the protein expressions of Bax, cleaved caspase-3, and cleaved PARP and upregulated the expression of Bcl-2 through reduced PI3K and pAKT expressions. Furthermore, our in vivo results indicated that quercetin improved retinal deformation and increased the thickness of both the outer nuclear layer and inner nuclear layer, whereas the expression of caspase-3 was inhibited. Taken together, these results demonstrate that quercetin could protect retinal pigment epithelium and the retina from NaIO3-induced cell apoptosis via reactive oxygen species-mediated mitochondrial dysfunction, involving the PI3K/AKT signaling pathway. This suggests that quercetin has the potential to prevent and delay AMD and other retinal diseases involving NaIO3-mediated apoptosis.

Thyroid hormone (TH) signaling plays an important role in the regulation of long-wavelength vision in vertebrates. In the retina, thyroid hormone receptor β (thrb) is required for expression of long-wavelength-sensitive opsin (lws) in red cone photoreceptors, while in retinal pigment epithelium (RPE), TH regulates expression of a cytochrome P450 enzyme, cyp27c1, that converts vitamin A₁ into vitamin A₂ to produce a red-shifted chromophore. To better understand how TH controls these processes, we analyzed the phenotype of zebrafish with mutations in the three known TH nuclear receptor transcription factors (thraa, thrab, and thrb). We found that no single TH nuclear receptor is required for TH-mediated induction of cyp27c1 but that deletion of all three (thraa −/−;thrab −/−;thrb −/−) completely abrogates its induction and the resulting conversion of A₁- to A₂-based retinoids. In the retina, loss of thrb resulted in an absence of red cones at both larval and adult stages without disruption of the underlying cone mosaic. RNA-sequencing analysis revealed significant down-regulation of only five genes in adult thrb −/− retina, of which three (lws1, lws2, and miR-726) occur in a single syntenic cluster. In the thrb −/− retina, retinal progenitors destined to become red cones were transfated into ultraviolet (UV) cones and horizontal cells. Taken together, our findings demonstrate cooperative regulation of cyp27c1 by TH receptors and a requirement for thrb in red cone fate determination. Thus, TH signaling coordinately regulates both spectral sensitivity and sensory plasticity.

Retinal neurodegeneration associated with the dysfunction or death of photoreceptors is a major cause of incurable vision loss. Tremendous progress has been made over the last two decades in discovering genes and genetic defects that lead to retinal diseases. The primary focus has now shifted to uncovering disease mechanisms and designing treatment strategies, especially inspired by the successful application of gene therapy in some forms of congenital blindness in humans. Both spontaneous and laboratory-generated mouse mutants have been valuable for providing fundamental insights into normal retinal development and for deciphering disease pathology. Here, we provide a review of mouse models of human retinal degeneration, with a primary focus on diseases affecting photoreceptor function. We also describe models associated with retinal pigment epithelium dysfunction or synaptic abnormalities. Furthermore, we highlight the crucial role of mouse models in elucidating retinal and photoreceptor biology in health and disease, and in the assessment of novel therapeutic modalities, including gene- and stem-cell-based therapies, for retinal degenerative diseases.

Rod and cone photoreceptors are highly similar in many respects but they have important functional and molecular differences. Here, we investigate genome-wide patterns of DNA methylation and chromatin accessibility in mouse rods and cones and correlate differences in these features with gene expression, histone marks, transcription factor binding, and DNA sequence motifs. Loss of NR2E3 in rods shifts their epigenomes to a more cone-like state. The data further reveal wide differences in DNA methylation between retinal photoreceptors and brain neurons. Surprisingly, we also find a substantial fraction of DNA hypo-methylated regions in adult rods that are not in active chromatin. Many of these regions exhibit hallmarks of regulatory regions that were active earlier in neuronal development, suggesting that these regions could remain undermethylated due to the highly compact chromatin in mature rods. This work defines the epigenomic landscapes of rods and cones, revealing features relevant to photoreceptor development and function. Vision in humans is made possible by a light-sensing sheet of cells at the back of the eye called the retina. The surface of the retina is populated by specialized sensory cells, known as rods and cones. The rod cells detect very dim light, while the cones are less sensitive to light but are used to detect color. Together, the rods and cones gather the information needed to create a picture that is then transmitted to the brain. Rods and cones have been studied for decades, and genetic analyses have revealed the patterns of gene expression that lead a cell to develop into either a rod or a cone. Researchers have also identified several key regulatory genes that control these patterns, but less is known about the role of other factors that control the expression of genes. Chemical modifications to DNA or modifications to the proteins associated with DNA – which are collectively called epigenetic modifications – can either promote or inhibit the activation of nearby genes. Now, Mo et al. have shown that rods and cones from mice have very different patterns of epigenetic modifications. The experiments also revealed that many sections of DNA that are marked to promote gene activation contain known rod-specific or cone-specific genes; and that rod cells need a known regulatory gene to develop their specific pattern of epigenetic modifications. Finally, Mo et al. showed that epigenetic regulation differed between brain cells and rods and cones. These insights into epigenetic regulation of rod and cone genes may help explain why some people with eye diseases caused by the same genetic mutation may develop symptoms at different ages or lose vision at different rates. The new information about gene regulation may also help scientists to reprogram stem cells to become healthy rods or cones that could be transplanted into people with eye disease to restore their vision.

The critical role of epigenetic modification of histones in maintaining the normal function of the nervous system has attracted increasing attention. Among these modifications, the level of histone acetylation, modulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is essential in regulating gene expression. In recent years, the research progress on the function of HDACs in retinal development and disease has advanced remarkably, while that regarding HATs remains to be investigated. Here, we overview the roles of HATs and HDACs in regulating the development of diverse retinal cells, including retinal progenitor cells, photoreceptor cells, bipolar cells, ganglion cells, and Müller glial cells. The effects of HATs and HDACs on the progression of various retinal diseases are also discussed with the highlight of the proof-of-concept research regarding the application of available HDAC inhibitors in treating retinal diseases.

S cones expressing the short wavelength-sensitive type 1 (SWS1) class of visual pigment generally form only a minority type of cone photoreceptor within the vertebrate duplex retina. Hence, their primary role is in color vision, not in high acuity vision. In mammals, S cones may be present as a constant fraction of the cones across the retina, may be restricted to certain regions of the retina or may form a gradient across the retina, and in some species, there is coexpression of SWS1 and the long wavelength-sensitive (LWS) class of pigment in many cones. During retinal development, SWS1 opsin expression generally precedes that of LWS opsin, and evidence from genetic studies indicates that the S cone pathway may be the default pathway for cone development. With the notable exception of the cartilaginous fishes, where S cones appear to be absent, they are present in representative species from all other vertebrate classes. S cone loss is not, however, uncommon; they are absent from most aquatic mammals and from some but not all nocturnal terrestrial species. The peak spectral sensitivity of S cones depends on the spectral characteristics of the pigment present. Evidence from the study of agnathans and teleost fishes indicates that the ancestral vertebrate SWS1 pigment was ultraviolet (UV) sensitive with a peak around 360 nm, but this has shifted into the violet region of the spectrum (>380 nm) on many separate occasions during vertebrate evolution. In all cases, the shift was generated by just one or a few replacements in tuning-relevant residues. Only in the avian lineage has tuning moved in the opposite direction, with the reinvention of UV-sensitive pigments.

Background Melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) respond directly to light and have been shown to mediate a broad variety of visual behaviors in adult animals. ipRGCs are also the first light sensitive cells in the developing retina, and have been implicated in a number of retinal developmental processes such as pruning of retinal vasculature and refinement of retinofugal projections. However, little is currently known about the properties of the six ipRGC subtypes during development, and how these cells act to influence retinal development. We therefore sought to characterize the structure, physiology, and birthdate of the most abundant ipRGC subtypes, M1, M2, and M4, at discrete postnatal developmental timepoints. Methods We utilized whole cell patch clamp to measure the electrophysiological and morphological properties of ipRGC subtypes through postnatal development. We also used EdU labeling to determine the embryonic timepoints at which ipRGC subtypes terminally differentiate. Results Our data show that ipRGC subtypes are distinguishable from each other early in postnatal development. Additionally, we find that while ipRGC subtypes terminally differentiate at similar embryonic stages, the subtypes reach adult-like morphology and physiology at different developmental timepoints. Conclusions This work provides a broad assessment of ipRGC morphological and physiological properties during the postnatal stages at which they are most influential in modulating retinal development, and lays the groundwork for further understanding of the specific role of each ipRGC subtype in influencing retinal and visual system development.