Early Gene expression changes after axonal injury
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE11862 | GEO | 2008/09/01
SECONDARY ACCESSION(S): PRJNA105665
REPOSITORIES: GEO
Similar Datasets
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:The failure of adult CNS neurons to survive and regenerate their axons after injury or in neurodegenerative disease remains a major target for basic and clinical neuroscience. Recent data demonstrated in the adult mouse that exogenous expression of Sry-related high-mobility-box 11 (Sox11) promotes optic nerve regeneration after optic nerve injury, but exacerbates the death of a subset of retinal ganglion cells, alpha-RGCs. During development, Sox11 is required for RGC differentiation from retinal progenitor cells (RPCs), and we found that mutation of a single residue to prevent sumoylation at K91 increased nuclear localization and RGC differentiation in vitro. Here we explored whether this Sox11 manipulation similarly has stronger effects on RGC survival and optic nerve regeneration. In vitro, we found that non-SUMOylatable Sox11 K91A leads to RGC death and suppresses axon outgrowth in primary neurons. We furthermore found that Sox11 K91A more strongly promotes axon regeneration but also increases RGC death after optic nerve injury in vivo in adult mouse. RNA-seq data showed that Sox11 and Sox11 K91A increase the expression of key signaling pathway genes associated with axon growth and regeneration but downregulated Spp1 and Opn4 expression in RGC cultures, consistent with negatively regulating the survival of α-RGCs and ipRGCs. Thus Sox11 and its sumoylation site at K91 regulate gene expression, survival and axon growth in RGCs and may be explored further as potential regenerative therapies for optic neuropathy.
2021-01-15 | GSE160627 | GEO
Project description:The death of retinal ganglion cells(RGC) after the damage on optic nerve as a result of high intraocular pressure is the main reason of the irreversible blindness in glaucoma patients ,and mammals have very limited ability of maintaining the RGCs after optic nerve injury.Zebrafish,however,possess the ability of keep most RGCs from death after optic nerve injury. The purpose of this study is to determine which gene or pathway mediate the RGC survival mechanism underlying.It is observed JAK/STAT signaling pathway as well as the innate immune response is activated after optic nerve injury(in this study,optic nerve transection).Pharmacological inhibition of JAK/STAT by intravitreal(IV) injection of JAK inhibitor,P6,induced the reduction of RGC survival while both local and systemic immune suppressor application result in the rescue of RGC survival.Moreover,phospho-STAT3(pSTAT3),which is an evidence of STAT3 activation,demonstrated elevation of expression level after ONT,and the trend of pSTAT3 expression change is consistent with the RGC survival rate change .JAK inhibition reduced pSTAT3 expression level and immune suppressor application elevated the pSTAT3 expression level on RGCs. In summary,these data suggested JAK/STAT signaling pathway crosstalk with innate immune response create a dynamic balance in the mechanism of RGC survival.Interestingly,innate immune response which was used to be considered promoting tissue repair in other studies,proved to be suppressing RGC survival in this study.These data could be used as reference for future direction of neuroprotection in glaucoma treatment.
2021-10-05 | GSE171426 | GEO
Project description:Retinal ganglion cells (RGCs) convey the major output of information collected from the eye to the brain. RGCs are irreversibly lost when injured in degenerative diseases such as glaucoma; this failure can be partially reversed by eliminating the retinal mobile zinc (Zn2+) and leads to substantial axon regeneration. ZnT3 conditional knockout in retinal amacrine cells blocks the synaptic transport of Zn2+, which promotes RGC survival and axonal regeneration in optic nerve jinjury (ONC). Here, we conducted an mRNA sequencing of flow cytometry-isolated RGCs 3 days after optic nerve injury with or without ZnT3 expression in retinal amacrine cells.
2023-07-01 | GSE213937 | GEO
Project description:Goals of the study: 1. Assess the gene expression profile in rat RGC after experimental IOP elevation to elucidate the molecular mechanisms of RGC death. 2. Identify potentially novel genes and pathways that may contribute to RGC death in glaucoma. Background: Glaucoma is a neurodegenerative disease characterized by the slow, progressive degeneration of RGC. Elevated IOP is the biggest risk factor for developing glaucoma, loss of RGC and optic nerve atrophy. The pathophysiology of glaucomatous neurodegeneration is not fully understood. It is now clear that RGC die by apoptosis in glaucoma. However, what triggers the apoptosis is still unknown. So far, several gene expression studies have been performed on the retina as a whole. These studies revealed up and downregulation of many genes in response to elevated IOP and optic nerve transection. However, the retina is a complex tissue composed of neuronal, glial and vascular cell types. The RGCs only comprise 5% or less of retinal cells. The gene expression profiles from whole retina can not represent of RGC gene expression. In the current study, we sought to investigate the whole genome regulation of the RGCs in glaucoma. The study was carried out in 3 adult male Brown Norway rats with experimental glaucoma. An equal number of RGCs were captured from normal eyes and eyes with elevated IOP. Gene expression in the glaucomatous RGC was compared with that in the fellow RGC by using Affymetrix Gene chip.
2010-10-01 | E-GEOD-12596 | biostudies-arrayexpress
Project description:Retinal ganglion cell (RGC) death is the final consequence of many blinding diseases, where there is considerable variation in the time course and severity of RGC loss. Indeed, this process appears to be influenced by a wide variety of genetic and environmental factors. In this study we explored the genetic basis for differences in ganglion cell death in two inbred strains of mice. We found that RGCs are more susceptible to death following optic nerve crush in C57BL/6J mice (54% survival) than in DBA2/J mice (62% survival). Using the Illumina Mouse-6 microarray, we identified 1,580 genes with significant change in expression following optic nerve crush in these two strains of mice. Our analysis of the changes occurring after optic nerve crush demonstrated that the greatest amount of change (44% of the variance) was due to the injury itself. This included changes associated with ganglion cell death, reactive gliosis, and abortive regeneration. The second pattern of gene changes (23% of the variance) was primarily related to differences in gene expressions observed between the C57BL/6J and DBA/2J mouse strains. The remaining changes in gene expression represent interactions between the effects of optic nerve crush and the genetic background of the mouse. We extracted one genetic network from this dataset that appears to be related to tissue remodeling. One of the most intriguing sets of changes included members of the crystallin family of genes, which may represent a signature of pathways modulating the susceptibility of cells to death. Differential responses to optic nerve crush between two widely used strains of mice were used to define molecular networks associated with ganglion cell death and reactive gliosis. These results form the basis for our continuing interest in the modifiers of retinal injury. 18 Samples: 9 per strain (C57BL/6J & DBA/2J); 3 conditions per strain
2010-08-19 | E-GEOD-17117 | biostudies-arrayexpress
Project description:Purpose: This study aims to the downstream transcriptional networks controlled by JUN and DDIT which are critical for RGC death Methods: RNA was isolated from the retinas of wild-type mice and mice deficient in Jun, Ddit3, and both Jun and Ddit3 three days after mechanical optic nerve crush injury (CONC), and was subjected to RNA-sequecing. Results: This study identified downstream transcriptional changes after injury included both neuronal survival and pro-inflammatory signaling that were attenuated to differing degrees by loss of Ddit3, Jun, and Ddit3/Jun. Conclusion: These data suggest pro-inflammatory signaling in the retina might be secondary to activation of pro-death pathways in RGCs after acute axonal injury. These results determine the downstream transcriptional networks important for apoptotic signaling which may be important for ordering and staging the pro-degenerative signals after mechanical axonal injury.
2022-03-24 | GSE168789 | GEO
Project description:Analysis of retinal ganglion cells (RGCs) by scRNA-seq is emerging as a state-of-the-art method for studying RGC biology and subtypes, as well as for studying the mechanisms of neuroprotection and axon regeneration in the central nervous system (CNS). Rbpms has been established as a pan-RGC marker, and Spp1 has been established as an αRGC type and macrophage marker. Here, we analyzed by scRNA-seq retinal microglia and macrophages, and found Rbpms+ subpopulations of retinal microglia/macrophages, which pose a potential pitfall in scRNA-seq studies involving RGCs. We performed comparative analysis of cellular identity of the presumed RGC cells isolated in recent scRNA-seq studies, and found that Rbpms+ microglia/macrophages confounded identification of RGCs. We also showed using immunohistological analysis that, Rbpms protein localizes to stress granules in a subpopulation of retinal microglia after optic nerve injury, which was further supported by bioinformatics analysis identifying stress granule-associated genes enriched in the Rbpms+ microglia/macrophages. Our findings suggest that the identification of Rbpms+ RGCs by immunostaining after optic nerve injury should exclude cells in which Rbpms signal is restricted to a subcellular granule, and include only those cells in which the Rbpms signal is labeling cell soma diffusely. Finally, we provide solutions for circumventing this potential pitfall of Rbpm-expressing microglia/macrophages in scRNA-seq studies, by including in RGC and αRGC selection criteria other pan-RGC and αRGC markers.
2023-05-23 | GSE228986 | GEO
Project description:Loss of specialized neurons in neurodegenerative diseases and after nerve injury is mediated in a neuronal subtype- and region-specific fashion. However, little is known about what molecular contexts define selective vulnerability. Here, we demonstrate that retinal ganglion cells (RGCs) in the mouse peripheral ventrotemporal (VT) retina are the most susceptible to optic nerve injury. Mechanistically, we show that the ventral-specific molecule, the serotonin transporter (SERT) is upregulated on VT axons within one day after injury and loss of SERT attenuates VT RGC death and promotes axon regeneration. From RNA-seq analysis, the transmembrane protein Gpnmb has been identified as a target downregulated by SERT. Moreover, GPNMB is involved in RGC protection and axon regeneration. Together, our studies reveal the serotonin transporter as a determinant of selective vulnerability.
2020-07-11 | GSE153812 | GEO
Project description:Since retinal ganglion cells (RGCs) do not regenerate after injury, RGC replacement therapy could provide an approach to vision restoration in glaucoma and other optic neuropathies. Here we developed a rapid protocol for direct induction of RGC (iRGC) differentiation from human iPSCs and ESCs in less than two weeks, by overexpression of NGN2 in RGC survival-promoting medium supplemented with a Notch inhibitor. Neuronal morphology and neurite growth were observed within one week of induction. Immunostaining and qRT-PCR for characteristic RGC-specific genes confirmed identity. Calcium imaging was used to evaluate iRGCs’ electrophysiologic maturation, and demonstrated GABA-induced excitatory calcium influx characteristic of immature RGCs. Using single cell-RNA sequencing (scRNA-seq) we further delineated iRGCs’ differentiation and compared iRGC transcriptomic profiles to fetal human and retinal organoid-derived RGCs. Unbiased clustering showed high similarities of transcriptomic profiles among iRGCs, early-stage fetal human RGCs and early-stage retinal organoid-derived RGCs. However, for some markers, including BRN3a, BRN3b and NEFL, iRGCs demonstrated expression patterns more similar to fetal RGCs than to retinal organoid RGCs. After intravitreal injection into rodent eyes, transplanted iRGCs survived and migrated into host retinas where they were detected one week and one month after transplant. Prior optic nerve trauma to the recipient host did not significantly enhance or detract from iRGC integration, but iRGCs protected host RGCs from neurodegeneration. Taken together, these data demonstrate rapid iRGC generation in vitro into an immature cell with high similarity to human fetal RGCs and capacity for retinal integration after transplant, including after optic nerve injury. The simplicity of this system may benefit translational studies on human RGCs.
2022-04-10 | GSE200452 | GEO