Spatial and Single-cell Transcriptomic Characterization of WIF1-induced Normal-tension Glaucoma [Visium]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE293380 | GEO | 2025/05/09
REPOSITORIES: GEO
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Project description:To explore the potential roles of WIF1 upregulation in glaucoma pathogenesis, we performed WIF1 overexpression in mouse retina via AAV delivery and then assessed its impact on IOP, retinal visual function, and RGC survival. We found it causes visual function defects and RGC loss, especially the RGCs from periphery retina. Our integrative analyses from single cell RNA-seq, ATAC-seq, and spatial transcriptomics have further uncovered the dynamic signaling changes from various retinal cells to RGCs. And our spatial transcriptomics results have also revealed the various changes of central and peripheral RGCs after WIF1 overexpression.
2025-05-09 | GSE293381 | 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: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.
2010-10-01 | GSE12596 | GEO
Project description:Elevated intraocular pressure (IOP) is the major risk factor for glaucoma, a sight threatening disease of retinal ganglion cells (RGCs) and their axons. Despite the central importance of IOP, details of the impact of IOP elevation on RGC gene expression remain elusive. We developed a novel 4-step immunopanning protocol to extract adult mouse RGCs with high fidelity and used it to isolate RGCs from wild type mice exposed to 2 weeks of IOP elevation generated by the microbead model. IOP was elevated to 2 distinct levels which were defined as Mild (IOP increase >1mmHg and <4mmHg) and Moderate (IOP increase > 4mmHg). RNA sequencing was used to compare the transcriptional environment at each IOP level. Differentially expressed genes were markedly different between the 2 groups, and pathway analysis revealed frequently opposed responses between the IOP levels. These results suggest that the magnitude of IOP elevation has a critical impact on RGC transcriptional changes. Furthermore, it is possible that an IOP-based set point exists within RGCs to impact the direction of transcriptional change. It is possible that this improved understanding of changes in RGC gene expression can ultimately lead to novel diagnostics and therapeutics for glaucoma.
2019-02-22 | GSE122205 | GEO
Project description:Retinal ganglion cells (RGCs) are the sole output neurons conveying visual stimuli from the retina to the brain and the dysfunction or loss of RGCs is the primary determinant of visual loss in traumatic and degenerative ocular conditions. Currently, there is a lack of RGC-specific Cre mouse lines that serve as invaluable tools for manipulating genes in RGCs and studying the genetic basis of RGC diseases. The RNA-binding protein with multiple splicing (RBPMS) is identified as the specific marker of all RGCs. Here, we report the generation and characterization of a knock-in mouse line in which a P2A-CreERT2 coding sequence is fused in-frame to the C-terminus of endogenous RBPMS, allowing the co-expression of RBPMS and CreERT2. The inducible Rbpms-CreERT2 mice exhibited a high recombination efficiency in activating the expression of tdTomato reporter gene in nearly all adult RGCs as well as in differentiated RGCs starting at E13.5. Additionally, heterozygous Rbpms-CreERT2 knock-in mice showed no detectable defect in the retinal structure, visual function and transcriptome. Altogether, our results demonstrated that the Rbpms-CreERT2/+ knock-in mouse can serve as a powerful and highly desired genetic tool for lineage tracing, genetic manipulation, retinal physiology study and ocular disease modeling in RGCs.
2023-08-21 | GSE232726 | GEO
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:Retinal ganglion cells (RGCs) are the projection neurons of the retina. Proper development of the axon and dendrite of RGCs is the basis for these cells to function as projection neurons to deliver visual information to the brain. The purpose of this study was to investigate the function of a newly identified RGC-specific gene, Shtn1, in neurite development in RGCs. Using IF, we demonstrated that SHTN1 is distinctively expressed in RGCs during the period in which RGCs actively develop and adjust the connections of their neurites with upstream and downstream neurons. Using the iRGC system, we demonstrated that Shtn1 promotes the growth and complexity of neurites, and thus the electrophysiological maturation, of iRGCs. RNA-Seq analyses showed that Shtn1 may also regulate gene expression and neurogenesis in iRGCs. These findings improve our understanding of the molecular machinery governing RGC neurite development, and may help to optimize future RGC regeneration methods.
2024-07-10 | GSE254839 | GEO
Project description:Retinal ganglion cells (RGCs) form an array of feature detectors, which transmit visual information through segregated channels to central brain regions. Characterizing RGC diversity is required to understand the logic of this functional parcellation. Using single- cell transcriptomics, we systematically classified RGCs in adult and larval zebrafish, thereby identifying marker genes for >30 stable and several transient cell types, cell type-specific markers, and their maturational changes. We used this catalog to engineer transgenic driverreporter lines, enabling experimental genetic access to specific RGC types. Strikingly, expression of a few transcription factors often predicts dendrite morphological features, in particular and axonal projections to specific tectal layers and extratectal targets. Moreover, iIn vivo calcium imaging revealed that molecularly defined RGCs exhibit highly specific functional tuningphysiological properties. Finally, chemogenetic ablation of eomesa+ RGCs, which comprise three melanopsin-expressing types with a specific projections to thalamus, pretectum and one deep tectal layerpattern, selectively impaired a visual behavior, phototaxis. Our study establishes a framework and provides a resource for systematically studying the functional architecture of the visual system.
2020-11-30 | GSE152842 | GEO
Project description:RGC differentiation is tightly controlled by extrinsic and intrinsic factors. Growth and differentiation factor 15 (GDF-15) promotes RGC differentiation, opposite to GDF-11 which inhibits RGC differentiation, both in the mouse retina and in human stem cells. To deepen our understanding of how these two closely related molecules confer opposing effects on retinal development, here we assess the transcriptional profiles of mouse retinal progenitors exposed to exogenous GDF-11 or -15. We find a dichotomous effect of GDF-15 on RGC differentiation, decreasing RGCs expressing residual pro-proliferative genes and increasing RGCs expressing non-proliferative genes, suggestive of greater RGC maturation. Furthermore, GDF-11 promoted the differentiation of photoreceptors and amacrine cells. These data enhance our understanding of the mechanisms underlying the differentiation of RGCs and photoreceptors from retinal progenitors and suggest new approaches to the optimization of protocols for the differentiation of these cell types.
2024-05-16 | GSE252861 | GEO
Project description:Retinal ganglion cells (RGCs) are the projection neurons of the retina. In early retinal progenitor cells (RPCs), Atoh7 orchestrates the developmental RGC program and regulates the expression of critical downstream targets, including Pou4f factors. The absence of Pou4f2 or more POU4F family genes results in defects in RGC differentiation, aberrant axonal elaboration and ultimately RGC death, confirming the requirement of POU4F factors for RGC development and survival, with a critical role in regulating RGC axon outgrowth and pathfinding. Here, we investigated in vivo whether ectopic Pou4f2 expression in late retinal progenitor cells (late RPCs) is sufficient to induce the generation of cells with RGC properties, including projecting axons to the brain. Using a strong ubiquitous promoter to induce Pou4f2 overexpression in neonates, we observed a change in targeted cell distribution in the retinal tissue, including the presence of cells in the ganglion cell layer and inner plexiform layer. Single-cell RNA sequencing (scRNA-seq) analysis shows that several RGC-genes (Rbpms, Gap-43, Hs6st3, and Foxp2) are upregulated after Pou4f2 overexpression. Additionally, gene ontology analysis indicates the induction of genes related to axonogenesis and neuronal differentiation. Imaging throughout the visual pathway revealed high density of axons projecting toward the optic nerve head and extending to brain, such as the superior colliculus and geniculate nucleus. Thus, Pou4f2 induced neurons with specific RGC characteristics that share similarities with resident RGCs and notably project axons that reach brain targets. In conclusion, these results showed that POU4F2 alone was sufficient to promote aspects of RGC development and axon projection, inducing critical properties of projection neurons from retinal progenitors outside their developmental window.
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