Gene Expression Profile From 15 day Embryonic Mouse Eyes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE174287 | GEO | 2021/05/12
REPOSITORIES: GEO
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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:In mammalian albinism, disrupted melanogenesis in the retinal pigment epithelium (RPE) is associated with fewer retinal ganglion cells (RGCs) projecting ipsilaterally to the brain, resulting in numerous abnormalities in the retina and visual pathway, especially binocular vision. To further understand the molecular link between disrupted RPE and a reduced ipsilateral RGC projection in albinism, we compared gene expression in the embryonic albino and pigmented mouse RPE.
2018-10-25 | GSE121467 | GEO
Project description:Glaucoma is a common ocular disorder that is a leading cause of blindness worldwide. It is characterized by the dysfunction and loss of retinal ganglion cells (RGCs). Although many studies have implicated various molecules in glaucoma, no mechanism has been shown to be responsible for the earliest detectable damage to RGCs and their axons in the optic nerve. Here, we show that the leukocyte transendothelial migration pathway is activated in the optic nerve head at the earliest stages of disease in an inherited mouse model of glaucoma. This resulted in proinflammatory monocytes entering the optic nerve prior to detectable neuronal damage. A 1-time x-ray treatment prevented monocyte entry and subsequent glaucomatous damage. A single x-ray treatment of an individual eye in young mice provided that eye with long-term protection from glaucoma but had no effect on the contralateral eye. Localized radiation treatment prevented detectable neuronal damage and dysfunction in treated eyes, despite the continued presence of other glaucomatous stresses and signaling pathways. Injection of endothelin-2, a damaging mediator produced by the monocytes, into irradiated eyes, combined with the other glaucomatous stresses, restored neural damage with a topography characteristic of glaucoma. Together, these data support a model of glaucomatous damage involving monocyte entry into the optic nerve. Genome-wide assessment of gene expression changes was performed in DBA/2J-Gpnmb+, DBA/2J mice and irradiated DBA/2J mice at 8.5 and 10.5 months of age.
2012-03-28 | GSE36833 | GEO
Project description:In an attempt to repair injured central nervous system (CNS) nerves/tracts, immune cells are recruited into the injury site, but endogenous response in adult mammals is insufficient for promoting regeneration of severed axons. Here, we found that a portion of retinal ganglion cell (RGC) CNS projection neurons that survive after optic nerve crush (ONC) injury are enriched for and upregulate fibronectin (Fn)-interacting integrins Itga5 and ItgaV, and that Fn promotes long-term survival and long-distance axon regeneration of a portion of axotomized adult RGCs in culture. We then show that, Fn is developmentally downregulated in the axonal tracts of optic nerve and spinal cord, but injury-activated macrophages/microglia upregulate Fn while axon regeneration-promoting zymosan augments their recruitment (and thereby increases Fn levels) in the injured optic nerve. Finally, we found that Fn’s RGD motif, established to interact with Itga5 and ItgaV, promotes long-term survival and long-distance axon regeneration of adult RGCs after ONC in vivo, with some axons reaching the optic chiasm when co-treated with Rpl7a gene therapy. Thus, experimentally augmenting Fn levels in the injured CNS is a promising approach for therapeutic neuroprotection and axon regeneration of at least a portion of neurons.
2024-06-28 | GSE269812 | GEO
Project description:In an attempt to repair injured central nervous system (CNS) nerves/tracts, immune cells are recruited into the injury site, but endogenous response in adult mammals is insufficient for promoting regeneration of severed axons. Here, we found that a portion of retinal ganglion cell (RGC) CNS projection neurons that survive after optic nerve crush (ONC) injury are enriched for and upregulate fibronectin (Fn)-interacting integrins Itga5 and ItgaV, and that Fn promotes long-term survival and long-distance axon regeneration of a portion of axotomized adult RGCs in culture. We then show that, Fn is developmentally downregulated in the axonal tracts of optic nerve and spinal cord, but injury-activated macrophages/microglia upregulate Fn while axon regeneration-promoting zymosan augments their recruitment (and thereby increases Fn levels) in the injured optic nerve. Finally, we found that Fn’s RGD motif, established to interact with Itga5 and ItgaV, promotes long-term survival and long-distance axon regeneration of adult RGCs after ONC in vivo, with some axons reaching the optic chiasm when co-treated with Rpl7a gene therapy. Thus, experimentally augmenting Fn levels in the injured CNS is a promising approach for therapeutic neuroprotection and axon regeneration of at least a portion of neurons.
2024-06-28 | GSE269813 | GEO
Project description:The retina constitutes a segment of the central nervous system (CNS). Both retinal and CNS neurons lack the inherent capacity to spontaneously regenerate axons following injury. Retinal ganglion cells (RGCs) serve as the neurons connecting the eyes to the brain. Diseases such as glaucoma initiate damage to RGC axons at the optic nerve, ultimately leading to cell death and irreversible vision loss. While enhancing the survival of RGCs is a crucial initial step, especially for those with pre-existing axonal injuries in the optic nerve due to prolonged insults, effective therapies should also promote axon regeneration. Neuro-regeneration and reintegration into the brain remain to be enormous challenges in neurology and ophthalmology. Despite decades of effort and resources invested in the research of neuro-regeneration, scientists are still rather far from comprehensively identifying all intrinsic axonal growth regulators and their collaborative roles. Data-independent acquisition mass spectrometry (DIA-MS) is a next-generation proteomic methodology that generates permanent digital proteome maps offering highly reproducible retrospective analysis of cellular and tissue specimens. Compared to conventional mass-spectrometry, DIA-MS provides better reproducibility and sensitivity. In this study, we employed DIA-MS to conduct a comprehensive protein expression mapping in retinas from mouse models of degeneration and regeneration, and to gain insights into the complex molecular mechanisms associated with degeneration and regeneration processes in the retina.
2024-07-29 | PXD049992 | Pride
Project description:The resident astrocytes-retinal ganglion cell lipoxin circuit is impaired during retinal stress that include exocytotoxic- and ocular hypertension-induced neuropathy. Two endogenous lipoxins (Lipoxin A4 and Lipoxin B4) produced by homeostatic astrocytes directly act on RGCs. LXB4 is the most potent lipoxin in the retina and directly increases RGC survival and function in ocular hypertension-induced neuropathy. Homeostatic roles and cellular targets of LXB4 in the retina and optic nerve are a critical gap in knowledge. Single-cell RNA sequencing was used to define cellular targets and signaling of LXB4 in the retina. For modeling neurodegeneration, sustained ocular hypertension was induced by silicone-oil injection in the anterior chamber of mouse eyes. For morphological characterization of microglia populations in the retina and optic nerve, we used MorphOMICs and pseudotime trajectory analysis. Bulk RNA sequencing of optic nerves was performed to characterize pathways and mechanism of action for LXB4. qPCR and immunohistochemistry were used for validation of transcriptomics data. Student’s t-test and one-way ANOVA were used to determine differences between experimental groups. Single Cell transcriptomic identified microglia as a primary target for LXB4 in the healthy retina. LXB4 downregulated genes that drive microglia environmental sensing and reactivity responses. Analysis of microglia function uncovered that ocular hypertension induces distinct, temporally defined and dynamic phenotypes in the retina and, unexpectedly, in the distal myelinated optic nerve. Microglial expression of CD74, a marker of disease-associated microglia (DAM) in the brain, was only induced in a unique population of optic nerve microglia but not the retina. Genetic deletion of lipoxin formation correlated with presence of a CD74 optic nerve microglia population in normotensive eyes optic, while LXB4 treatment during ocular hypertension shifted optic nerve microglia toward a homeostatic morphology and non-reactive state and downregulated expression of CD74. Furthermore, we identified a correlation between CD74 and phospho-PI3K (p-PI3K) expression levels in the optic nerve, that was reduced by LXB4 treatment. Results identify distal optic nerve microglial dynamic and reactive responses as a key feature of ocular hypertension induce neurodegeneration. Our findings establish microglia regulation as a new LXB4 cell target in the retina and optic nerve. LXB4 maintenance of optic nerve microglia homeostatic phenotype and inhibition of a disease-associated phenotype are potential mechanisms for LXB4 neuroprotection.
2024-04-10 | GSE251716 | GEO
Project description:The resident astrocytes-retinal ganglion cell lipoxin circuit is impaired during retinal stress that include exocytotoxic- and ocular hypertension-induced neuropathy. Two endogenous lipoxins (Lipoxin A4 and Lipoxin B4) produced by homeostatic astrocytes directly act on RGCs. LXB4 is the most potent lipoxin in the retina and directly increases RGC survival and function in ocular hypertension-induced neuropathy. Homeostatic roles and cellular targets of LXB4 in the retina and optic nerve are a critical gap in knowledge. Single-cell RNA sequencing was used to define cellular targets and signaling of LXB4 in the retina. For modeling neurodegeneration, sustained ocular hypertension was induced by silicone-oil injection in the anterior chamber of mouse eyes. For morphological characterization of microglia populations in the retina and optic nerve, we used MorphOMICs and pseudotime trajectory analysis. Bulk RNA sequencing of optic nerves was performed to characterize pathways and mechanism of action for LXB4. qPCR and immunohistochemistry were used for validation of transcriptomics data. Student’s t-test and one-way ANOVA were used to determine differences between experimental groups. Single Cell transcriptomic identified microglia as a primary target for LXB4 in the healthy retina. LXB4 downregulated genes that drive microglia environmental sensing and reactivity responses. Analysis of microglia function uncovered that ocular hypertension induces distinct, temporally defined and dynamic phenotypes in the retina and, unexpectedly, in the distal myelinated optic nerve. Microglial expression of CD74, a marker of disease-associated microglia (DAM) in the brain, was only induced in a unique population of optic nerve microglia but not the retina. Genetic deletion of lipoxin formation correlated with presence of a CD74 optic nerve microglia population in normotensive eyes optic, while LXB4 treatment during ocular hypertension shifted optic nerve microglia toward a homeostatic morphology and non-reactive state and downregulated expression of CD74. Furthermore, we identified a correlation between CD74 and phospho-PI3K (p-PI3K) expression levels in the optic nerve, that was reduced by LXB4 treatment. Results identify distal optic nerve microglial dynamic and reactive responses as a key feature of ocular hypertension induce neurodegeneration. Our findings establish microglia regulation as a new LXB4 cell target in the retina and optic nerve. LXB4 maintenance of optic nerve microglia homeostatic phenotype and inhibition of a disease-associated phenotype are potential mechanisms for LXB4 neuroprotection.
2024-04-10 | GSE250615 | GEO
Project description:Axon pathfinding is a key step during the formation of neural circuits but however the transcriptional mechanisms regulating its progression remain poorly understood. The binary decision of crossing or avoiding the midline that neurons make during developmente midline that mammalian retinal ganglion cell (RGC) axons take at the optic chiasm has classically represented a robust model to search for novel mechanisms controlling the selection of axonal trajectories. Here, in order to identify new axon pathfinding regulators, we compared the transcriptome and chromatin accessibility profiles of mammalian retinal ganglion cells RGCs projecting ipsilateral (iRGCs) or contralaterally (cRGCs). Overall, our analyses retrieved dozens of new molecules potentially involved in axon pathfinding and uncovered the regulatory logic behind axon trajectories selection.
2022-08-22 | GSE184275 | GEO
Project description:The lack of neuroprotective treatments for retinal ganglion cells (RGCs) and optic nerve (ON) is a central challenge for glaucoma management. Emerging evidence suggests that redox factor NAD+ decline is a hallmark of aging and neurodegenerative diseases including glaucoma. Supplementation with NAD+ precursors and overexpression of the nicotinamide mononucleotide adenylyltransferase (NMNAT), the key enzyme involved in the NAD+ biosynthetic process, have significant neuroprotection effect on glaucoma. Among the three NMNAT isoforms, only NMNAT2 is enriched in neurons, especially in axons, however, its role in glaucoma is not well studied. Here we present the expression levels of the enzymes that involved in NAD+ metabolism in both naïve and glaucomatous mouse RGCs. Intriguingly, NMNAT2 is the dominant form of NMNATs in RGCs and only its mRNA level, but not NMNAT1 or NMNAT3, is significant decreased in glaucomatous RGCs. We then demonstrated proof-of-principal gene therapy strategy of restoring RGC-specific NMNAT2 and NAD+ levels by AAV2-mediated RGC-specific promoter mSncg-driven long half-life NMNAT2 mutant. This gene therapy strategy is further tested in two optic neuropathy models, traumatic ON crush model and ocular hypertension glaucoma model. RGC-specific NMNAT2 overexpression significantly promotes RGC somata and axons survival and preserves visual function in both models. Our studies suggest that the weaking of NMNAT2 expression in glaucomatous RGCs contributes to detrimental NAD+ decline and that modulating RGC intrinsic NMNAT2 level by AAV2-mSncg vector is a potent gene therapy for glaucomatous neuroprotection.
2021-08-22 | GSE182483 | GEO