Distinct signature of altered homeostasis in aging rod photoreceptors: Implications for retinal diseases
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE22317 | GEO | 2010/06/15
SECONDARY ACCESSION(S): PRJNA127547
REPOSITORIES: GEO
Similar Datasets
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
Project description:Photoreceptor disorders are collectively known as retinal degeneration (RD), and include retinitis pigmentosa (RP), cone-rod dystrophy and age related macular degeneration (AMD). These disorders are largely genetic in origin; individual mutations in any one of >200 genes cause RD, making mutation specific therapies prohibitively expensive. A better treatment plan, particularly for late stage disease, may involve stem cell transplants into the photoreceptor or ganglion cell layers of the retina. Stem cells from young mouse retinas can be transplanted, and can form photoreceptors in adult retinas. These cells can be grown in tissue culture, but can no longer form photoreceptors. We have used microarrays to investigate differences in gene expression between cultured retinal progenitor cells (RPCs) that have lost photoreceptor potential, postnatal day 1 (pn1) retinas and the postnatal day 5 (pn5) retinas that contain transplantable photoreceptors. We have also compared FACS sorted Rho-eGFP expressing rod photoreceptors from pn5 retinas with Rho-eGFP negative cells from the same retinas. We have identified over 300 genes upregulated in rod photoreceptor development in multiple comparisons, 37 of which have been previously identified as causative of retinal disease when mutated. It is anticipated that this research should bring us closer to growing photoreceptors in culture and therefore better treatments for RD. This dataset is also a resource for those seeking to identify novel retinopathy genes in RD patients. We extracted whole retinas from postnatal day 1 (Pn1) and postnatal day 5 (Pn5) mice, and compared them with cultured RPCs derived from pn5 retinas, using Affymetrix mouse 430A_2 arrays. We also extracted cells from Rho-eGFP Pn5 retinas and FACS sorted them. GFP+ve cells represent immature rod photoreceptors, as they express the Rho-eGFP fusion protein, which is only expressed in rods. GFP-ve cells represent all other retinal neurons. These samples were amplified and compared using Affymetrix mouse 430A_2arrays, by Source Biosciences GMBH, Berlin, Germany. Results from immature rods were then compared with those from other retinal neurons, while results from whole Pn5 retinas were compared with Pn1 retinas (which don't yet express rod specific genes), and RPCs, which are glial precursors. RPCs were also compared with Pn1 retinas. Genes which showed changed expression profiles in at least 3/4 of comparisons were prioritised for further investigation.
2015-01-20 | E-GEOD-59201 | biostudies-arrayexpress
Project description:Aging-associated functional decline and disease susceptibility are believed to be mediated, at least in part, through alterations in the epigenome. To explore epigenetic changes that might influence visual function with advanced age, we performed whole genome bisulfite sequencing of purified mouse rod photoreceptors at four different ages and identified 2054 genomic regions that gain or lose DNA methylation. Differentially methylated regions (DMRs) clustered at chromosomal hotspots, especially on Chromosome 10 that included a longevity interactome. DMRs were preferentially detected at an early stage of aging in long neuronal genes and in rod-specific regulatory regions containing open chromatin domains and H3K27 acetylation. Integration of methylome to age-related transcriptome changes, chromatin signatures and first order protein-protein interactions uncovered an enrichment of DMRs in pathways associated with aging, longevity, synaptic function, and energy homeostasis. In concordance, we detected reduced mitochondrial maximum reserve capacity with retinal age in ex vivo assays. Our study reveals age-dependent genomic and chromatin features susceptible to DNA methylation changes in rod photoreceptors and identifies associations with established and cell type-specific pathways altered in aging.
2020-03-10 | GSE134872 | GEO
Project description:Photoreceptor disorders are collectively known as retinal degeneration (RD), and include retinitis pigmentosa (RP), cone-rod dystrophy and age related macular degeneration (AMD). These disorders are largely genetic in origin; individual mutations in any one of >200 genes cause RD, making mutation specific therapies prohibitively expensive. A better treatment plan, particularly for late stage disease, may involve stem cell transplants into the photoreceptor or ganglion cell layers of the retina. Stem cells from young mouse retinas can be transplanted, and can form photoreceptors in adult retinas. These cells can be grown in tissue culture, but can no longer form photoreceptors. We have used microarrays to investigate differences in gene expression between cultured retinal progenitor cells (RPCs) that have lost photoreceptor potential, postnatal day 1 (pn1) retinas and the postnatal day 5 (pn5) retinas that contain transplantable photoreceptors. We have also compared FACS sorted Rho-eGFP expressing rod photoreceptors from pn5 retinas with Rho-eGFP negative cells from the same retinas. We have identified over 300 genes upregulated in rod photoreceptor development in multiple comparisons, 37 of which have been previously identified as causative of retinal disease when mutated. It is anticipated that this research should bring us closer to growing photoreceptors in culture and therefore better treatments for RD. This dataset is also a resource for those seeking to identify novel retinopathy genes in RD patients.
2015-01-20 | GSE59201 | GEO
Project description:Aging-associated functional decline and disease susceptibility are believed to be mediated, at least in part, through alterations in the epigenome. To explore epigenetic changes that might influence visual function with advanced age, we performed whole genome bisulfite sequencing of purified mouse rod photoreceptors at four different ages and identified 2054 genomic regions that gain or lose DNA methylation. Differentially methylated regions (DMRs) clustered at chromosomal hotspots, especially on Chromosome 10 that included a longevity interactome. DMRs were preferentially detected at an early stage of aging in long neuronal genes and in rod-specific regulatory regions containing open chromatin domains and H3K27 acetylation. Integration of methylome to age-related transcriptome changes, chromatin signatures and first order protein-protein interactions uncovered an enrichment of DMRs in pathways associated with aging, longevity, synaptic function, and energy homeostasis. In concordance, we detected reduced mitochondrial maximum reserve capacity with retinal age in ex vivo assays. Our study reveals age-dependent genomic and chromatin features susceptible to DNA methylation changes in rod photoreceptors and identifies associations with established and cell type-specific pathways altered in aging.
2020-03-10 | GSE134871 | GEO
Project description:Aging-associated functional decline and disease susceptibility are believed to be mediated, at least in part, through alterations in the epigenome. To explore epigenetic changes that might influence visual function with advanced age, we performed whole genome bisulfite sequencing of purified mouse rod photoreceptors at four different ages and identified 2054 genomic regions that gain or lose DNA methylation. Differentially methylated regions (DMRs) clustered at chromosomal hotspots, especially on Chromosome 10 that included a longevity interactome. DMRs were preferentially detected at an early stage of aging in long neuronal genes and in rod-specific regulatory regions containing open chromatin domains and H3K27 acetylation. Integration of methylome to age-related transcriptome changes, chromatin signatures and first order protein-protein interactions uncovered an enrichment of DMRs in pathways associated with aging, longevity, synaptic function, and energy homeostasis. In concordance, we detected reduced mitochondrial maximum reserve capacity with retinal age in ex vivo assays. Our study reveals age-dependent genomic and chromatin features susceptible to DNA methylation changes in rod photoreceptors and identifies associations with established and cell type-specific pathways altered in aging.
2020-03-10 | GSE137935 | GEO
Project description:Generation of three-dimensional (3D) organoids with optic cup like structures from pluripotent stem cells has created opportunities for investigating mammalian retinal development in vitro. However, retinal organoids in culture do not completely reflect the developmental state and in vivo architecture of the rod-dominant mouse retina. To assess rod photoreceptor differentiation in retinal organoids, we took advantage of Nrl-GFP mice that show rod-specific expression of GFP directed by the promoter of leucine zipper transcription factor NRL. Using embryonic and induced pluripotent stem cells (ESCs and iPSCs, respectively) derived from the Nrl-GFP mouse, we were successful in establishing long-term retinal organoid cultures (up to day 35) using modified culture conditions (called High Efficiency Hypoxia Induced Generation of Photoreceptors in Retinal Organoids, or HIPRO). We demonstrate efficient differentiation of pluripotent stem cells to retinal structures, with over 70% of embryoid bodies forming optic vesicles at Day (D)7, >50% producing optic cups by D10, and a majority of these surviving until at least D35. The HIPRO organoids include distinct inner retina neurons in somewhat stratified architecture and mature Müller glia spanning the entire retina. Almost 70% of the cells in retinal organoids are rod photoreceptors that exhibit elongated cilia. Transcriptome profiles of GFP+ rod photoreceptors, purified from organoids at Day 25-35, demonstrate a high correlation to gene profiles of purified rods from mouse retina at postnatal day (P) 2 to 6, indicating their early state of differentiation. Our 3D retinal organoids thus closely mimic in vivo retinogenesis and provide an efficient in vitro model to investigate photoreceptor development and modeling disease pathology.
2016-09-09 | GSE86790 | GEO
Project description:Cone photoreceptors are the primary initiator of visual transduction in the human retina. Dysfunction or death of rod photoreceptors precedes cone loss in many retinal and macular degenerative diseases, suggesting a rod-dependent trophic support for cone survival. Rod differentiation and homeostasis are dependent on the basic motif leucine zipper transcription factor NRL. The loss of Nrl in mice (Nrl-/-) results in a retina with predominantly S-opsin containing cones that exhibit molecular and functional characteristics of WT cones. Here we report that Nrl-/- retina undergoes a rapid but transient period of degeneration in early adulthood, with cone apoptosis, retinal detachment, alterations in retinal vessel structure, and activation and translocation of retinal microglia. However, cone degeneration stabilizes by four months of age, resulting in a thinned but intact outer nuclear layer with residual cones expressing S- and M-opsins and a preserved photopic ERG. At this stage, microglia translocate back to the inner retina and reacquire a quiescent morphology. Gene profiling analysis during the period of transient degeneration reveals misregulation of stress response and inflammation genes, implying their involvement in cone death. The Nrl-/- retina illustrates the long-term viability of cones in the absence of rods and may serve as a model for elucidating mechanisms of cone homeostasis and degeneration that would be relevant to understanding diseases of the cone-dominant human macula. Targets were generated from a pair of retinas (one Nrl-/- mouse) per biological replicate. Four biological replicates were generated for each of the five aging timepoints (1, 2, 4, 6, and 10 months post natal).
2011-11-15 | E-GEOD-33674 | biostudies-arrayexpress
Project description:Mutation of rod photoreceptor-enriched transcription factors is a major cause of inherited blindness. We identified the orphan nuclear hormone receptor ERRβ as selectively expressed in rod photoreceptors. Overexpression of ERRβ induces expression of rod-specific genes in retinas of both wildtype and in Nrl-/- mice, which lack rod photoreceptors. Mutation of ERRβ results in dysfunction and degeneration of rods, while inverse agonists of ERRβ trigger rapid rod degeneration, which is rescued by constitutively active mutants of ERRβ. ERRβ coordinates expression of multiple genes that are rate-limiting regulators of ATP generation and consumption in photoreceptors. Furthermore, enhancing ERRβ activity rescues photoreceptor defects that result from loss of the photoreceptor-specific transcription factor Crx. Our findings demonstrate that ERRβ is a critical regulator of rod photoreceptor function and survival, and suggest that ERRβ 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 ERRβ knockout versus wildtype.
2010-07-30 | E-GEOD-21944 | biostudies-arrayexpress
Project description:Rod-derived Cone Viability Factor (RdCVF) is a truncated thioredoxin secreted by rod photoreceptors that protects cones. Because the secondary loss of cones in retinitis pigmentosa (RP) is the major visual handicap of this untreatable neurodegenerative disease, the administration of RdCVF is thought to be a promising therapy for RP. We show that RdCVF is acting by binding to Basigin-1 (BSG1) at the surface of cones. BSG1 is an alternative splice product of the BSG gene, a transmembrane protein with an extra immunoglobin domain expressed specifically in the retina. BSG1 binds to the glucose transporter GLUT1. RdCVF increases glucose entry into cones. We found that the increase in glucose is used by cones to induce cell survival by stimulating aerobic glycolysis. A disease associated missense mutation of RdCVF results in its inability to bind to BSG1, to stimulate glucose uptake and to prevent secondary cone death of a model of RP.
2016-06-15 | PXD001715 | Pride