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[E-MEXP-3786] IGF-I-induced chronic gliosis and retinal stress lead to neurodegeneration in an animal model of retinopathy

ABSTRACT: Transcription profiling by array of mouse male retinas to investigate IGF-I-induced chronic gliosis and retinal stress IGF-I exert multiple effects in different retinal cell populations in both physiological and pathological conditions. Transgenic mice overexpressing IGF-I in the retina showed impaired electroretinographic responses at 6-7 months of age that worsen with age. This retinal neuronal dysfunction was correlated with the loss of rod photoreceptors, bipolar, ganglion and amacrines cells. Neuronal alterations were preceded by the overexpression of retinal stress markers, acute phase proteins and gliosis-related genes. IGF-I overexpression leads to chronic gliosis and microgliosis in TgIGF-I retinas, with mild oxidative stress, impaired recycling of glutamate and defective potassium buffering. These impaired supportive functions can contribute to neurodegeneration in TgIGF-I retinas, together with the increased production of pro-inflammatory cytokines, potential mediators of neuronal death.

ORGANISM(S): Mus musculus

PROVIDER: GSE46246 | GEO | 2013/04/30

SECONDARY ACCESSION(S): PRJNA198461

REPOSITORIES: GEO

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[E-MEXP-3786] IGF-I-induced chronic gliosis and retinal stress lead to neurodegeneration in an animal model of retinopathy

Project description:Transcription profiling by array of mouse male retinas to investigate IGF-I-induced chronic gliosis and retinal stress IGF-I exert multiple effects in different retinal cell populations in both physiological and pathological conditions. Transgenic mice overexpressing IGF-I in the retina showed impaired electroretinographic responses at 6-7 months of age that worsen with age. This retinal neuronal dysfunction was correlated with the loss of rod photoreceptors, bipolar, ganglion and amacrines cells. Neuronal alterations were preceded by the overexpression of retinal stress markers, acute phase proteins and gliosis-related genes. IGF-I overexpression leads to chronic gliosis and microgliosis in TgIGF-I retinas, with mild oxidative stress, impaired recycling of glutamate and defective potassium buffering. These impaired supportive functions can contribute to neurodegeneration in TgIGF-I retinas, together with the increased production of pro-inflammatory cytokines, potential mediators of neuronal death. 3 transgenic and 3 wild type biological replicates examined.

2013-04-30 | E-GEOD-46246 | biostudies-arrayexpress

IGF-I-induced chronic gliosis and retinal stress lead to neurodegeneration in an animal model of retinopathy

Project description:IGF-I exert multiple effects in different retinal cell populations in both physiological and pathological conditions. Transgenic mice overexpressing IGF-I in the retina showed impaired electroretinographic responses at 6-7 months of age that worsen with age. This retinal neuronal dysfunction was correlated with the loss of rod photoreceptors, bipolar, ganglion and amacrines cells. Neuronal alterations were preceded by the overexpression of retinal stress markers, acute phase proteins and gliosis-related genes. IGF-I overexpression leads to chronic gliosis and microgliosis in TgIGF-I retinas, with mild oxidative stress, impaired recycling of glutamate and defective potassium buffering. These impaired supportive functions can contribute to neurodegeneration in TgIGF-I retinas, together with the increased production of pro-inflammatory cytokines, potential mediators of neuronal death.

2013-08-01 | E-MEXP-3786 | biostudies-arrayexpress

APOE4-promoted gliosis and degeneration in tauopathy are ameliorated by pharmacological inhibition of HMGB1 release

Project description:Apolipoprotein E4 (APOE4) is an important driver of Tau pathology, gliosis, and degeneration in Alzheimer’s disease (AD). Still, the mechanisms underlying these APOE4-driven pathological effects remain elusive. In this study, we demonstrated in a tauopathy mouse model that APOE4 promoted the nucleo-cytoplasmic translocation and release of high mobility group box 1 (HMGB1) from hippocampal neurons, which correlated with the severity of hippocampal microgliosis and degeneration. Injection of HMGB1 into the hippocampus of young APOE4-tauopathy mice induced considerable and persistent gliosis. Selective removal of neuronal APOE4 reduced the nucleo-cytoplasmic translocation and release of HMGB1. Therapeutic treatment of APOE4-tauopathy mice with HMGB1 inhibitors effectively blocked the intraneuronal translocation and release of HMGB1 and ameliorated the development of prominent APOE4-driven AD pathologies, including gliosis, Tau pathology, neurodegeneration, and myelin deficits. Single-nucleus RNA-sequencing revealed that treatment with HMGB1 inhibitors diminished disease-associated and enriched disease-protective subpopulations of neurons, microglia, and astrocytes in APOE4-tauopathy mice. Thus, HMGB1 inhibitors represent a promising approach for treating APOE4-related AD.

2023-09-01 | GSE242153 | GEO

E-MEXP-3786

Project description:Transcription profiling by array of mouse male retinas to investugate IGF-I-induced chronic gliosis and retinal stress

2015-10-22 | E-MEXP-3786 | ExpressionAtlas

Glutamatergic neuronal activity regulates retinal angiogenesis and blood-retinal barrier via Norrin/b-catenin signaling

Project description:Interactions among neuroglial and vascular components are crucial for retinal angiogenesis and blood-retinal barrier (BRB) maturation. Neuronal synaptic dysfunctions precede vascular abnormalities in many retinal pathologies. However, whether neuronal activity, specifically glutamatergic activity, regulates retinal angiogenesis and BRB maturation remains unclear. Using in vivo genetic studies in mice, single-cell RNA-sequencing and functional validation, we found that deep plexus angiogenesis and paracellular BRB maturation are delayed in Vglut1-/- retinas, where neurons fail to release glutamate. In contrast, deep plexus angiogenesis and paracellular BRB maturation are accelerated in Gnat1-/- retinas, where constitutively depolarized rods release excess glutamate. Mechanistically, Norrin expression and endothelial Norrin/b-catenin signaling are downregulated in Vglut1-/- retinas, and upregulated in Gnat1-/- retinas. Pharmacological activation of endothelial Norrin/ b-catenin signaling in Vglut1-/- retinas rescued both deep plexus angiogenesis and paracellular BRB integrity. Thus, our findings demonstrate that glutamatergic neuronal activity regulates retinal angiogenesis and BRB maturation by modulating Norrin/b-catenin signaling.

2024-06-27 | GSE235993 | GEO

Neuronal APOE4 removal strongly protects against Tau-mediated gliosis, neurodegeneration, and myelin deficits

Project description:Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD). Conditions of stress or injury induce APOE expression within neurons, but the exact roles of neuronal APOE4 in AD pathogenesis are still unclear. Here we report a rigorous characterization of neuronal APOE4 effects on prominent AD-related pathologies by selectively removing APOE4 from neurons in an APOE4-expressing tauopathy mouse model. We found that the removal of neuronal APOE4 led to a drastic reduction in Tau pathology accumulation and spread, gliosis, neurodegeneration, neurodysfunction, and myelin deficits in this tauopathy mouse model. Single-nucleus RNA-sequencing revealed that the removal of neuronal APOE4 greatly diminished neurodegenerative disease-associated subpopulations of neurons, oligodendrocytes, astrocytes, and microglia that were enriched in APOE4-expressing tauopathy mice and whose accumulation correlated to the severity of Tau pathology, neurodegeneration, and myelin deficits. Thus, neuronal APOE4 plays a central role in promoting the development of major AD pathologies and its removal can effectively combat APOE4-driven effects in AD and other tauopathies.

2023-01-06 | GSE221215 | GEO

GENE EXPRESSION CHANGES WITHIN MM-CM-^\LLER GLIAL CELLS DURING RETINITIS PIGMENTOSA

Project description:Retinitis Pigmentosa (RP) is a progressive retinal degeneration in which the retina loses nearly all of its photoreceptor cells and undergoes major structural changes. Little is known regarding the role the resident glia, the MM-CM-<ller glia, play in the progression of the disease. Here we define gene expression changes in MM-CM-<ller glial cells (MGCs) from two different mouse models of RP, the retinal degeneration 1 (rd1) and rhodopsin knock-out (Rhod-ko) models. The RNA repertoire of 28 single MGCs was comprehensively profiled, and a comparison was made between MGC from wild type (WT) and mutant retinas. Two time points were chosen for analysis, one at the peak of rod photoreceptor death and one during the period of cone photoreceptor death. MGCs have been shown to respond to retinal degeneration by undergoing gliosis, a process marked by the upregulation of GFAP. In this data, many additional transcripts were found to change. These can be placed into functional clusters, such as retinal remodeling, stress response, and immune related response. It is noteworthy that a high degree of heterogeneity among the individual cells was observed, possibly due to their different spatial proximities to dying cells, and/or inherent heterogeneity among MGCs. Retinas were dissociated and single Muller Glial Cells were picked under a dissecting microscope using a micropipette based on their distinct morphological shape. Single cell cDNAs were generated and genome wide profiles were obtained by hybridization to Affymetrix 430 2.0 microarrays. Data was normalized using MAS5.0 software. A total of 28 Muller Glial Cells were analyzed and confirmed post hoc by expression of known marker genes.

2014-10-31 | E-GEOD-35386 | biostudies-arrayexpress

Characterization of the chromatin accessibility profile of Plagl1+/-pat retina

Project description:Retinal damage triggers reactive gliosis in Müller glia across vertebrate species, but only in regenerative animals, such as teleost fish, do Müller glia initiate repair; proliferating and undergoing neurogenesis to replace lost cells. We found that Plagl1, a maternally imprinted gene, is dynamically regulated in reactive Müller glia post-insult, with transcript levels transiently increasing before stably declining. To study Plagl1 retinal function, we examined Plagl1+/-pat null mutants postnatally, revealing defects in retinal architecture, visual signal processing and a reactive gliotic phenotype. Plagl1+/-pat Müller glia proliferate ectopically and give rise to inner retinal neurons and photoreceptors. Transcriptomic and ATAC-seq profiles revealed similarities between Plagl1+/-pat retinas and neurodegenerative and injury models, including an upregulation of pro-gliogenic and pro-proliferative pathways, such as Notch, not observed in wild-type retinas Plagl1 is thus an essential component of the transcriptional regulatory networks that retain mammalian Müller glia in quiescence.

2021-05-05 | GSE173853 | GEO

Characterization of the transcriptomic profile of Plagl1+/-pat retina

2021-05-06 | GSE173942 | GEO

Dynamic miRNA Expression Patterns During Retina Regeneration in Zebrafish: Loss of Dicer Inhibits Regeneration

Project description:Background: Adult zebrafish spontaneously regenerate their retinas after damage. Although a number of genes and signaling pathways involved in regeneration have been identified, the extent of mechanisms regulating regeneration is unclear. Small non-coding RNAs, microRNAs (miRNAs), that regulate regeneration of various tissues in lower vertebrates were examined for their potential roles in regulating zebrafish retinal regeneration. Results: To investigate the requirement of miRNAs during zebrafish retinal regeneration, we knocked down the expression of the miRNA-processing enzyme Dicer in retinas prior to light-induced damage. Dicer loss significantly reduced proliferation of Müller glia-derived neuronal progenitor cells during regeneration. To identify individual miRNAs with roles in retina regeneration, we collected retinas at different stages of light damage and performed small RNA high-throughput sequencing. We identified subsets of miRNAs that were differentially expressed during active regeneration but returned to basal levels once regeneration was completed. To validate the roles of differentially expressed miRNAs, we knocked down 6 different miRNAs that were upregulated in expression during regeneration and demonstrated that they have distinct effects on neuronal progenitor cell proliferation and migration during retina regeneration. Conclusions: miRNAs are necessary for retinal regeneration. miRNA expression is dynamic during regeneration. miRNAs function during initiation and progression of retinal regeneration. Identification of miRNAs before, during and after completion of zebrafish retinal regeneration

2014-09-20 | E-GEOD-58702 | biostudies-arrayexpress

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