Myeloid C3 causes neuronal injury prior to synapse loss [snMulti-ome-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE260978 | GEO | 2025/02/14
REPOSITORIES: GEO
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Project description:Complement component C3 mediates pathology in several CNS neurodegenerative diseases, but the cellular and molecular mechanisms leading to neuronal injury remain unclear. Herein, we examined how C3 deletion affects glial profiles and anterior visual pathway pathology in an animal model of neuroinflammation. scRNA-seq from mouse brain and optic nerve revealed that C3 expression defined disease-associated glial subtypes which were characterized by increased mTOR activation, cell metabolism, and translation. Deletion of C3 restored these glia towards homeostatic profiles. Myeloid-derived C3 mediated injury in optic nerve axons and retinal ganglion cells (RGCs) at the peak of EAE. To elucidate the timing of pathology we examined retinas prior to symptom onset and found reductions in Brn3a, an RGC transcription factor involved in dendritic arborization and protection from apoptosis. Our study supports a direct role for C3 in activating the mTOR-ribosomal biogenesis axis in glia which subsequently mediate early neuro-axonal stress and later synapse loss.
2025-02-14 | GSE260983 | GEO
Project description:Complement component C3 mediates pathology in several CNS neurodegenerative diseases, but the cellular and molecular mechanisms leading to neuronal injury remain unclear. Herein, we examined how C3 deletion affects glial profiles and anterior visual pathway pathology in an animal model of neuroinflammation. scRNA-seq from mouse brain and optic nerve revealed that C3 expression defined disease-associated glial subtypes which were characterized by increased mTOR activation, cell metabolism, and translation. Deletion of C3 restored these glia towards homeostatic profiles. Myeloid-derived C3 mediated injury in optic nerve axons and retinal ganglion cells (RGCs) at the peak of EAE. To elucidate the timing of pathology we examined retinas prior to symptom onset and found reductions in Brn3a, an RGC transcription factor involved in dendritic arborization and protection from apoptosis. Our study supports a direct role for C3 in activating the mTOR-ribosomal biogenesis axis in glia which subsequently mediate early neuro-axonal stress and later synapse loss.
2025-02-14 | GSE260982 | GEO
Project description:We used optic nerve injury as a model to study early signaling events in the neuronal soma following axonal injury. Optic nerve injury results in the selective death of retinal ganglion cells (RGCs). The time course of cell death takes place over a period of days with the earliest detection of RGC death at about 48 hr post injury. We hypothesized that in the period immediately following axonal injury, there are changes in the soma that signal surrounding glia and neurons and that start programmed cell death. In the current study, we investigated early changes in cellular signaling and gene expression that occur within the first 6 hrs post optic nerve injury. We detected differences in phosphoproteins and gene expression within this time period that we used to interpret temporal events. Our studies revealed that the entire retina has been signaled by the RGC soma within 30 min after optic nerve injury and that pathways that modulate cell death are likely to be active in RGCs within 6 hrs following axonal injury Experiment Overall Design: In the treated animals, axons of the optic nerve were crushed with fine forceps for 10 sec, 1 mm posterior to the globe, under direct visualization, within an intact meningeal sheath. Controls were contralateral eyes from the same animals in each group that had not been injured. After 6 hr eyes were enucleated and processed for tissue sectionin
2008-10-25 | E-GEOD-11862 | biostudies-arrayexpress
Project description:Reactive astrocytes are typically studied in models that cause irreversible mechanical damage to axons, neuronal cell bodies, and glia. We evaluated the response of astrocytes in the optic nerve head to a subtle injury induced by a brief, mild elevation of the intraocular pressure. Astrocytes demonstrated reactive remodeling showing hypertrophy, process retraction and simplification of their shape. We used microarray to indentify differentially expressed genes and to investigate the molecular mechanisms of astrogliosis in response to this subtle injury. Six- to eight-week old C57Bl/6 male mice were used in this experiment. One eye underwent an elevation in intraocular pressure to 30 mmHg for 1 hour and then allowed to recover for 3 days. The contralateral eye served as a control. Due to the small tissue size of the mouse optic nerve head, two optic nerve heads were pooled together for each microarray chip. We used 10 mice to generate five biological replicates for each condition.
2013-05-17 | E-GEOD-40009 | biostudies-arrayexpress
Project description:We used optic nerve injury as a model to study early signaling events in the neuronal soma following axonal injury. Optic nerve injury results in the selective death of retinal ganglion cells (RGCs). The time course of cell death takes place over a period of days with the earliest detection of RGC death at about 48 hr post injury. We hypothesized that in the period immediately following axonal injury, there are changes in the soma that signal surrounding glia and neurons and that start programmed cell death. In the current study, we investigated early changes in cellular signaling and gene expression that occur within the first 6 hrs post optic nerve injury. We detected differences in phosphoproteins and gene expression within this time period that we used to interpret temporal events. Our studies revealed that the entire retina has been signaled by the RGC soma within 30 min after optic nerve injury and that pathways that modulate cell death are likely to be active in RGCs within 6 hrs following axonal injury Keywords: Stress Response
2008-09-01 | GSE11862 | GEO
Project description:Epigenetic regulation of the genome through DNA modifications, mainly methylcytosine (mC) and hydroxymethylcytosine (hmC), alters DNA accessibility, genomic organization and gene expression and is thought to be altered during neurodegenerative diseases, such as age-related macular degeneration (AMD). Analysis of retina epigenetic and transcriptomic signatures at the cell-type specific level is crucial to understanding the pathophysiology of retinal degeneration. We have discovered that Aldh1l1 is specifically expressed in the major macroglia of the retina, the Müller glia, and, unlike the brain, is not expressed in retinal astrocytes. This allows a novel model to study paired epigenetic and transcriptomic signatures in Müller glia using Nuclear Tagging and Translating Ribosome Affinity Purification (NuTRAP) for temporally controlled labeling and isolation of Müller glial DNA and RNA. As validated through a variety of approaches, the Aldh1l1cre/ERT2-NuTRAP model provides Müller glia specific translatome and epigenome profiles. Application of this approach to models of acute injury (optic nerve crush) and chronic stress (aging) uncovered common Müller glia-specific transcriptome changes in inflammatory pathways, as well as differential signatures for each stimulus. The expression of components of the IL1b signalling axis, complement system, and markers of gliosis was enhanced in Müller glia in response to optic nerve crush but not in response to aging. The expression of components of the purinergic receptor and focal adhesion signalling pathways changed uniquely in response to aging but not with optic nerve crush. The Aldh1l1cre/ERT2-NuTRAP model allows focusing molecular analyses to a single, minority cell type within the retina, providing more substantial effect sizes than whole tissue analyses. The NuTRAP model, nucleic acid isolation, and validation approaches presented here can be applied to any retina cell type for which a cell type-specific cre is available.
2022-11-15 | GSE197509 | GEO
Project description:Epigenetic regulation of the genome through DNA modifications, mainly methylcytosine (mC) and hydroxymethylcytosine (hmC), alters DNA accessibility, genomic organization and gene expression and is thought to be altered during neurodegenerative diseases, such as age-related macular degeneration (AMD). Analysis of retina epigenetic and transcriptomic signatures at the cell-type specific level is crucial to understanding the pathophysiology of retinal degeneration. We have discovered that Aldh1l1 is specifically expressed in the major macroglia of the retina, the Müller glia, and, unlike the brain, is not expressed in retinal astrocytes. This allows a novel model to study paired epigenetic and transcriptomic signatures in Müller glia using Nuclear Tagging and Translating Ribosome Affinity Purification (NuTRAP) for temporally controlled labeling and isolation of Müller glial DNA and RNA. As validated through a variety of approaches, the Aldh1l1cre/ERT2-NuTRAP model provides Müller glia specific translatome and epigenome profiles. Application of this approach to models of acute injury (optic nerve crush) and chronic stress (aging) uncovered common Müller glia-specific transcriptome changes in inflammatory pathways, as well as differential signatures for each stimulus. The expression of components of the IL1b signalling axis, complement system, and markers of gliosis was enhanced in Müller glia in response to optic nerve crush but not in response to aging. The expression of components of the purinergic receptor and focal adhesion signalling pathways changed uniquely in response to aging but not with optic nerve crush. The Aldh1l1cre/ERT2-NuTRAP model allows focusing molecular analyses to a single, minority cell type within the retina, providing more substantial effect sizes than whole tissue analyses. The NuTRAP model, nucleic acid isolation, and validation approaches presented here can be applied to any retina cell type for which a cell type-specific cre is available.
2022-11-15 | GSE197507 | GEO
Project description:Epigenetic regulation of the genome through DNA modifications, mainly methylcytosine (mC) and hydroxymethylcytosine (hmC), alters DNA accessibility, genomic organization and gene expression and is thought to be altered during neurodegenerative diseases, such as age-related macular degeneration (AMD). Analysis of retina epigenetic and transcriptomic signatures at the cell-type specific level is crucial to understanding the pathophysiology of retinal degeneration. We have discovered that Aldh1l1 is specifically expressed in the major macroglia of the retina, the Müller glia, and, unlike the brain, is not expressed in retinal astrocytes. This allows a novel model to study paired epigenetic and transcriptomic signatures in Müller glia using Nuclear Tagging and Translating Ribosome Affinity Purification (NuTRAP) for temporally controlled labeling and isolation of Müller glial DNA and RNA. As validated through a variety of approaches, the Aldh1l1cre/ERT2-NuTRAP model provides Müller glia specific translatome and epigenome profiles. Application of this approach to models of acute injury (optic nerve crush) and chronic stress (aging) uncovered common Müller glia-specific transcriptome changes in inflammatory pathways, as well as differential signatures for each stimulus. The expression of components of the IL1b signalling axis, complement system, and markers of gliosis was enhanced in Müller glia in response to optic nerve crush but not in response to aging. The expression of components of the purinergic receptor and focal adhesion signalling pathways changed uniquely in response to aging but not with optic nerve crush. The Aldh1l1cre/ERT2-NuTRAP model allows focusing molecular analyses to a single, minority cell type within the retina, providing more substantial effect sizes than whole tissue analyses. The NuTRAP model, nucleic acid isolation, and validation approaches presented here can be applied to any retina cell type for which a cell type-specific cre is available.
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Project description:Epigenetic regulation of the genome through DNA modifications, mainly methylcytosine (mC) and hydroxymethylcytosine (hmC), alters DNA accessibility, genomic organization and gene expression and is thought to be altered during neurodegenerative diseases, such as age-related macular degeneration (AMD). Analysis of retina epigenetic and transcriptomic signatures at the cell-type specific level is crucial to understanding the pathophysiology of retinal degeneration. We have discovered that Aldh1l1 is specifically expressed in the major macroglia of the retina, the Müller glia, and, unlike the brain, is not expressed in retinal astrocytes. This allows a novel model to study paired epigenetic and transcriptomic signatures in Müller glia using Nuclear Tagging and Translating Ribosome Affinity Purification (NuTRAP) for temporally controlled labeling and isolation of Müller glial DNA and RNA. As validated through a variety of approaches, the Aldh1l1cre/ERT2-NuTRAP model provides Müller glia specific translatome and epigenome profiles. Application of this approach to models of acute injury (optic nerve crush) and chronic stress (aging) uncovered common Müller glia-specific transcriptome changes in inflammatory pathways, as well as differential signatures for each stimulus. The expression of components of the IL1b signalling axis, complement system, and markers of gliosis was enhanced in Müller glia in response to optic nerve crush but not in response to aging. The expression of components of the purinergic receptor and focal adhesion signalling pathways changed uniquely in response to aging but not with optic nerve crush. The Aldh1l1cre/ERT2-NuTRAP model allows focusing molecular analyses to a single, minority cell type within the retina, providing more substantial effect sizes than whole tissue analyses. The NuTRAP model, nucleic acid isolation, and validation approaches presented here can be applied to any retina cell type for which a cell type-specific cre is available.
2022-11-15 | GSE197500 | GEO
Project description:Epigenetic regulation of the genome through DNA modifications, mainly methylcytosine (mC) and hydroxymethylcytosine (hmC), alters DNA accessibility, genomic organization and gene expression and is thought to be altered during neurodegenerative diseases, such as age-related macular degeneration (AMD). Analysis of retina epigenetic and transcriptomic signatures at the cell-type specific level is crucial to understanding the pathophysiology of retinal degeneration. We have discovered that Aldh1l1 is specifically expressed in the major macroglia of the retina, the Müller glia, and, unlike the brain, is not expressed in retinal astrocytes. This allows a novel model to study paired epigenetic and transcriptomic signatures in Müller glia using Nuclear Tagging and Translating Ribosome Affinity Purification (NuTRAP) for temporally controlled labeling and isolation of Müller glial DNA and RNA. As validated through a variety of approaches, the Aldh1l1cre/ERT2-NuTRAP model provides Müller glia specific translatome and epigenome profiles. Application of this approach to models of acute injury (optic nerve crush) and chronic stress (aging) uncovered common Müller glia-specific transcriptome changes in inflammatory pathways, as well as differential signatures for each stimulus. The expression of components of the IL1b signalling axis, complement system, and markers of gliosis was enhanced in Müller glia in response to optic nerve crush but not in response to aging. The expression of components of the purinergic receptor and focal adhesion signalling pathways changed uniquely in response to aging but not with optic nerve crush. The Aldh1l1cre/ERT2-NuTRAP model allows focusing molecular analyses to a single, minority cell type within the retina, providing more substantial effect sizes than whole tissue analyses. The NuTRAP model, nucleic acid isolation, and validation approaches presented here can be applied to any retina cell type for which a cell type-specific cre is available.
2022-11-15 | GSE197481 | GEO