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Single-cell profiles of retinal neurons differing in resilience to injury reveal neuroprotective genes - Atlas of adult mouse retinal ganglion cells

ABSTRACT: Neuronal types in the central nervous system differ dramatically in their resilience to injury or insults. Here we studied selective resilience in mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC), which severs their axons and leads to death of ~80% of RGCs in 2 weeks. To identify expression programs associated with differential resilience, we first used single-cell RNA-seq (scRNA-seq) to generate a comprehensive molecular atlas of 45 RGC types in adult retina. We tracked their survival after ONC, characterized transcriptomic, morphological, and physiological changes that preceded degeneration, and identified genes selectively expressed by each type. Finally, loss- and gain-of-function assays in vivo showed that manipulating some of these genes improved neuronal survival and axon regeneration following ONC. This study provides a systematic framework for parsing type-specific responses to injury, and demonstrates that these responses can be used to reveal molecular targets for intervention.

ORGANISM(S): Mus musculus

PROVIDER: GSE133382 | GEO | 2019/11/27

REPOSITORIES: GEO

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Single-cell profiles of retinal neurons differing in resilience to injury reveal neuroprotective genes - Atlas of adult mouse retinal ganglion cells [Smart-seq2]

Project description:Neuronal types in the central nervous system differ dramatically in their resilience to injury or insults. Here we studied selective resilience in mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC), which severs their axons and leads to death of ~80% of RGCs in 2 weeks. To identify expression programs associated with differential resilience, we first used single-cell RNA-seq (scRNA-seq) to generate a comprehensive molecular atlas of 45 RGC types in adult retina. We tracked their survival after ONC, characterized transcriptomic, morphological, and physiological changes that preceded degeneration, and identified genes selectively expressed by each type. Finally, loss- and gain-of-function assays in vivo showed that manipulating some of these genes improved neuronal survival and axon regeneration following ONC. This study provides a systematic framework for parsing type-specific responses to injury, and demonstrates that these responses can be used to reveal molecular targets for intervention.

2019-11-27 | GSE137863 | GEO

Single-cell profiles of retinal neurons differing in resilience to injury reveal neuroprotective genes - Adult control RGCs treated with Actinomycin

2019-11-27 | GSE137828 | GEO

Single-cell profiles of retinal neurons differing in resilience to injury reveal neuroprotective genes - Time course of transcriptomic changes in single retinal ganglion cells following optic nerve crush

2019-11-27 | GSE137398 | GEO

Intercellular communication atlas reveals Oprm1 as a neuroprotective factor for retinal ganglion cells

Project description:The neuronal cell death results in neurodegenerative diseases. The extracellular environment plays a critical role in regulating cell viability. In this study, we explore how intercellular communication contributes to the survival of retinal ganglion cells (RGCs) following the optic nerve crush (ONC). By performing single-cell RNA-seq on whole retinal cells, we observed transcriptomic responses in non-RGC retinal cells to the injury, with astrocytes and Müller glia having the most interactions with RGCs. By comparing the RGC subclasses showing distinct resilience cell death, we identified top 47 interactions that are stronger in the high-survival RGCs, likely representing neuroprotective interactions. We performed functional assays on one of the receptors, Mu-opioid receptor (Oprm1). Although Oprm1 is preferentially expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs), its neuroprotective effect could be transferred to multiple RGC subclasses by specific overexpressing Oprm1 in pan-RGCs. Our study provides an atlas of cell-cell interactions in both intact and post-ONC retina and an effective strategy to predict molecular mechanisms in neuroprotection, underlying the principal role played by extracellular environment in supporting neuron survival.

2023-10-01 | GSE241268 | GEO

Direct-induced human retinal ganglion cells mimic fetal RGCs and are neuroprotective after transplant in vivo

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

Amacrine cells suppress retinal ganglion cells survival and optic nerve regeneration bu releasing intersynaptic zinc

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

Overlapping transcriptional programs promote survival and axonal regeneration of injured retinal ganglion cells [2]

Project description:Neurons of the central nervous system (CNS) display only a limited ability to survive and regenerate their axons after an injury. In mice, 85% of retinal ganglion cells (RGCs) die within 2 weeks of axotomy by optic nerve crush (ONC) and only few survivors regenerate axons. In the past years, a multitude of interventions have been identified to improve RGC survival and regeneration after an injury, however, each only protects a subset of neurons and stimulates axon regrowth in an even smaller set.. Here, we sought out to elucidate the molecular mechanisms underlying this selective responsiveness and investigated genes regulated by three well established survival and regeneration-promoting interventions – activation of the MTOR pathway via deletion of its inhibitor Pten, activation of the Jak/Stat-pathway by deletion of its endogenous inhibitor Socs3, and overexpression of the neurotrophic cytokine CNTF. Analysis of the transcriptomes from >125,000 single RGCs at various time points after ONC showed that while broad survival of all RGC types could be induced with each intervention, type-independent axon regeneration was only overcome with the manipulation of multiple pathways. Those RGCs were able to mitigate the injury response and simultaneously upregulated survival and regeneration associated programs (prior and after injury). Four independent ways of analysis identified these programs to be differentially regulated among RGCs, with distinct signatures for degenerating, surviving and regenerating cells. Finally, testing some genes associated with the regeneration-program in vivo identified potential future therapeutic targets to promote neuroprotection and axonal regeneration.

2022-06-28 | GSE202154 | GEO

Overlapping transcriptional programs promote survival and axonal regeneration of injured retinal ganglion cells [1]

2022-06-28 | GSE201254 | GEO

Single-cell profiles of retinal neurons differing in resilience to injury reveal neuroprotective genes - Adult control RGCs treated with Actinomycin

Project description:Single-cell profiles of retinal neurons differing in resilience to injury reveal neuroprotective genes - Adult control RGCs treated with Actinomycin

| PRJNA573602 | ENA

Effect of acupuncture treatments on retinal transcriptome after optic nerve injury

Project description:Purpose: We used RNA sequencing to investigate the effect of acupuncture treatment on retinal transcritome after optic nerve injury Methods: Retinal mRNA profiles of 5-week-old wild-type (WT), optic nerve crush injury (ONC), ONC injury with acupuncture treatment at acupoint GB20 (ONC-F) and ONC injury with acupuncture treatment at acupoint BL1 (ONC-J) mice were generated by deep sequencing, in triplicate, using Illumina Hiseq platform. The sequence reads that passed quality filters were analyzed with DESeq2 R package to identify differently expressed genes with padj<0.05. qRT–PCR validation was performed using TaqMan and SYBR Green assays Results: RNA-seq revealed that 436 genes including 31 transcription factors (TFs) were changed after injury, which include many well-known neural degeneration related TFs such as Jun, Ddit3, Atf3 and Atf4. Interestingly, acupuncture treatment at acupoint GB20 (Fengchi) or BL1(Jingming) after ONC injury both resulted in change of retinal gene expression, compared with ONC injury without treatment; furthermore, acupuncture treatment also reversed several gene expression status induced by axon injury. Conclusions: Our research first reported that acupuncture treatment after injury can regulated retinal transcriptome and reversed the gene expression level induced after injury, which will provide novel therapeutic targets for treatment of retinopathy diseases.

2019-11-12 | GSE131486 | GEO

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