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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Protective gene expression changes elicited by an inherited defect in photoreceptor structure.

ABSTRACT: To investigate pathogenic mechanisms in such instances, we have characterized rod photoreceptor and retinal gene expression changes in response to a defined insult to photoreceptor structure, using the retinal degeneration slow (rds) mouse model. Global gene expression profiling was performed on flow-sorted rds and wild-type rod photoreceptors immediately prior and subsequent to times at which OSs are normally elaborated. Dysregulated genes were identified via microarray hybridization, and selected candidates were validated using quantitative PCR analyses. We identified a single key gene, Egr1, that was dysregulated in a sustained fashion in rds rod photoreceptors and in the retina. Egr1 upregulation was associated with microglial activation and migration, into the outer retina at times subsequent to the major peak of photoreceptor cell death. Interestingly, this response was accompanied by neurotrophic factor upregulation. We hypothesize that activation of Egr1 and neurotrophic factors represents a protective immune mechanism, contributing to the characteristically slow retinal degeneration of the rds mouse model. We had two conditions WT and Rds-KO at 4 different time points: postnatal (P) 6, P9, P14 and P21.

ORGANISM(S): Mus musculus

SUBMITTER: Radu Cojocaru

PROVIDER: E-GEOD-33134 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Protective gene expression changes elicited by an inherited defect in photoreceptor structure.

Project description:To investigate pathogenic mechanisms in such instances, we have characterized rod photoreceptor and retinal gene expression changes in response to a defined insult to photoreceptor structure, using the retinal degeneration slow (rds) mouse model. Global gene expression profiling was performed on flow-sorted rds and wild-type rod photoreceptors immediately prior and subsequent to times at which OSs are normally elaborated. Dysregulated genes were identified via microarray hybridization, and selected candidates were validated using quantitative PCR analyses. We identified a single key gene, Egr1, that was dysregulated in a sustained fashion in rds rod photoreceptors and in the retina. Egr1 upregulation was associated with microglial activation and migration, into the outer retina at times subsequent to the major peak of photoreceptor cell death. Interestingly, this response was accompanied by neurotrophic factor upregulation. We hypothesize that activation of Egr1 and neurotrophic factors represents a protective immune mechanism, contributing to the characteristically slow retinal degeneration of the rds mouse model.

2011-12-31 | GSE33134 | GEO

A role for Prenylated rab acceptor 1 in vertebrate photoreceptor development

Project description:The rd1 mouse retina is a well-studied model of retinal degeneration where rod photoreceptors undergo cell death beginning at postnatal day P10 until P21. This period coincides with photoreceptor terminal differentiation in a normal retina. We have used the rd1 retina as a model to investigate early molecular defects in developing rod photoreceptors prior to the onset of degeneration. Using a microarray approach, we performed gene profiling comparing rd1 and wild type retinas at four time points starting at P2, prior to any obvious biochemical or morphological differences, and concluding at P8, prior to the initiation of cell death. We have identified genes that are differentially regulated in the rd1 retina at early time points, which may give insights into developmental defects that precede photoreceptor cell death. This is the first report of PRA1 expression in the retina. Our data support the hypothesis that PRA1 plays an important role in vesicular trafficking between the Golgi and cilia in differentiating and mature rod photoreceptors. Retinal samples were harvested from both rd1/le and wt animals at postnatal days 2, 4, 6, and 8 for microarray. Each sample included 8-14 retinas and experiments were performed in quadruplicate. Ten micrograms of total RNA was used for cDNA systhesis in target molecule production.

2012-11-02 | E-GEOD-41821 | biostudies-arrayexpress

Single-cell RNA sequencing of the retina in a model of retinitis pigmentosa reveals early responses to degeneration in rods and cones

Project description:In inherited retinal disorders such as retinitis pigmentosa (RP), rod photoreceptor-specific mutations cause primary rod degeneration that is followed by secondary cone death and loss of high-acuity vision. Mechanistic studies of retinal degeneration are challenging because of retinal heterogeneity. Moreover, the detection of early cone responses to rod death is especially difficult due to the paucity of cones in the retina. To resolve heterogeneity in the degenerating retina and investigate events in both types of photoreceptors during primary rod degeneration, we utilized droplet-based single-cell RNA sequencing in an RP mouse model, rd10.

2022-04-13 | GSE183206 | GEO

Transcription profiling of mouse rds mutant eye infected with CNTF/rAAV vs. control untreated eye

Project description:The retinal degeneration slow gene (rds/peripherin), is essential for normal photoreceptor (rods and cones) outer segment structure in the neurosensory retina. Our rds animal model, are stable transgenic mice that carry a null mutation (complete lost of function) in the rds gene. Those animals become blind, mimicking a human form of retinitis pigmentosa. In our experience we have observed dramatic levels of photoreceptor rescue after subretinal injection of those animals with a ciliary neurotrophic factor (CNTF) inserted into a recombinant Adeno-associate virus (rAAV) vector. However, this cell rescue is accompanied by changes in photoreceptor nuclear morphology, attenaution of the electroretinogram and evetually Apoptosis. By using Microarray analysis we hope to identify genes whose expression or lack thereof brings the cell to the brink of suicide. Identification of these genes will suggest therapeutic targets for the future. We will determine gene expression patterns in the retina of rds mice non-injected and injected with CNTF/rAAV virus after 60 days of injection. Our working hypothesis is that the injected CNTF/rAAV vector induces the expression of genes that somehow partially restores the photoreceptor morphology of rds mice. Paradoxically, it also has a negative effect on the phisiology of these cells (ERG). The up or down regulation of genes in different areas of the neurosensory retina collected by Laser Capture Microdissection will give us an insight on the relevance of candidate genes responsible for this phenomenon. We will use rds mice at age P25 and inject their rigth eye with CNTF/AVV virus (2.68x e13 particles/ml) and use the left eye as a control. Injection is performed via subretinal. Retinas will be collected at age P90 post injection. RNA will be extracted and processed accordingly for MIcroarray analysis.

2008-06-13 | E-GEOD-4756 | biostudies-arrayexpress

A role for Prenylated rab acceptor 1 in vertebrate photoreceptor development

2012-11-02 | GSE41821 | GEO

The orphan nuclear hormone receptor ERR-beta controls rod photoreceptor survival.

Project description:Mutation of rod photoreceptor-enriched transcription factors is a major cause of inherited blindness. We identified the orphan nuclear hormone receptor ERRÎ² as selectively expressed in rod photoreceptors. Overexpression of ERRÎ² induces expression of rod-specific genes in retinas of both wildtype and in Nrl-/- mice, which lack rod photoreceptors. Mutation of ERRÎ² results in dysfunction and degeneration of rods, while inverse agonists of ERRÎ² trigger rapid rod degeneration, which is rescued by constitutively active mutants of ERRÎ². ERRÎ² coordinates expression of multiple genes that are rate-limiting regulators of ATP generation and consumption in photoreceptors. Furthermore, enhancing ERRÎ² activity rescues photoreceptor defects that result from loss of the photoreceptor-specific transcription factor Crx. Our findings demonstrate that ERRÎ² is a critical regulator of rod photoreceptor function and survival, and suggest that ERRÎ² agonists may be useful in the treatment of certain retinal dystrophies. Affymetrix MOE430 microarrays were used to analyze the expression patterns of P21 mouse retinal tissues. The results were compared across the variable of Genotype, specifically ERRÎ² knockout versus wildtype.

2010-07-30 | E-GEOD-21944 | biostudies-arrayexpress

Retina-Specific Laminin 523 Drives Differentiation of Human Pluripotent Stem Cells to Photoreceptors [single cell_RNAseq]

Project description:Inherited retinal diseases and aged related macular degeneration are main causes of blindness that involves irreversible photoreceptor loss. Gene therapy approaches do not prevent photoreceptor degeneration during disease progression, and to date protocols for generating photoreceptors from pluripotent stem cells do not exist. Therefore, transplantation of photoreceptors containing retinal organoids is considered a potential option. However, in vitro formation of organoids requires animal-derived materials and they vary considerably in cell composition between batches, which strongly limits their applications in therapy. Here, we show that human recombinant retina-specific laminin isoform LN523, normally present in the extra cellular matrix ECM surrounding photoreceptors, supports differentiation of pluripotent embryonic stem cells to photoreceptor progenitors in vitro. Using a rabbit macular degeneration model, the transplanted and engrafted cells mature in vivo and form synaptic connectivity with the host retina. Furthermore, addition of a rod-derived cone viability factor increased the formation of cone photoreceptors. These results may pave the way for cell therapy treatment of macular degeneration.

2023-03-26 | GSE161416 | GEO

Retina-Specific Laminin 523 Drives Differentiation of Human Pluripotent Stem Cells to Photoreceptors [bulk_RNAseq]

2023-03-26 | GSE161414 | GEO

Distinct signature of altered homeostasis in aging rod photoreceptors: Implications for retinal diseases

Project description:To better understand the mechanistic basis of aging and its relationship with retinal degeneration, we examined gene expression changes in aging rod photoreceptors. Rod photoreceptor cell death is a feature of normal retinal aging and is accelerated in many retinal degenerative diseases, including AMD, the leading cause of untreatable adult blindness in the United States and other western countries. To our knowledge, the examination of age-related gene expression changes in a specific neuronal cell-type is novel, and it has allowed us to identify significant age-related changes with better resolution than is possible with whole retina samples. We used flow cytometry and a transgenic mouse with GFP-tagged rod photoreceptors to purify this specific cell population, and gene expression changes were evaluated at three time points using microarrays and quantitative RT-PCR. Our results suggest that aging is progressive, beginning even in young adult mice. Although rod photoreceptors are highly specialized neurons, our analyses revealed changes in consensus pathways of aging, including oxidative phosphorylation and stress responses affecting transcription and inflammation. In addition, we identified stress response processes that may be especially relevant for the aging retina and retinal diseases, such as angiogenesis and nuclear receptor signaling pathways that affect retinoid and lipid metabolism. We used flow cytometry and a transgenic mouse with GFP-tagged rod photoreceptors to purify this specific cell population, and gene expression changes were evaluated at three time points using microarrays and quantitative RT-PCR.

2010-06-14 | E-GEOD-22317 | biostudies-arrayexpress

RNA-Seq of mouse eye and retina tissues from wild type and Nrl transcription factor knockout mice

Project description:The initial aim of this work was to understand the pathophysiology of Enhanced S-cone Syndrome (ESCS) that leads to retinal degeneration. Although ESCS was identified in humans decades ago and since then the causative genes have been elucidated, our understanding of the accompanying retinal degeneration is still poorly understood. Knockout of the Nrl transcription factor in mice produces a retina overpopulated with S-cone like photoreceptors along with absence of rod photoreceptors and recapitulates many of the phenotypic features seen in human ESCS patients. We wanted to study this murine model through a combinatorial genetic and structural approach to improve understanding of the disease process that leads to photoreceptor degeneration and blindness, potentially guiding future therapies. By using RNA-Sequencing (RNA-Seq) to examine mature wild type and Nrl-/- ocular tissues, we were able to determine global changes in their transcriptomes. The massively parallel RNA-sequencing experiment revealed new insight into the transcriptional mis-regulation in the ESCS murine model and revealed a change in gene expression in putative proteins involved in photoreceptor phagocytosis. Key photoreceptor ligands necessary for phagocyotsis, Tub and Tulp1, were down-regulated in the Nrl-/- retina. Down regulation of key retinoid metabolic genes, coupled with down-regulation of Tub and Tulp1, suggested a potential mechanism involving defective phagocytosis underlies the photoreceptor degeneration seen in ESCS. We report RNA-Seq experiments of whole eye and retinal tissues from wild type and Nrl transcription factor knockout mice on the C57BL/6 background. Examine two different ocular tissues in two mouse models of varying photoreceptor populations

2011-06-07 | E-GEOD-29752 | biostudies-arrayexpress

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