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Single-nucleus RNA-seq of enriched retinal ganglion cells (RGCs) with RGC-specific overexpression of hOprm1 under optic nerve crush injury condition

ABSTRACT: Through a comparative analysis of RGC subclasses exhibiting varying levels of resilience to cell death, based on cell-cell interaction analysis, we identified the Mu-opioid receptor, encoded by the Oprm1 gene, as a novel neuroprotective factor for pan-RGCs. Functionally and with the sequencing dataset deposited here, we validated Oprm1 as a neuroprotective factor for RGCs, by demonstrating that overexpression of Oprm1 in RGCs not only led to a markedly increased survival rate of RGCs following several different types of retinal injuries, but also significantly improved visually-guided perception behaviors.

ORGANISM(S): Mus musculus

PROVIDER: GSE248537 | GEO | 2023/12/26

REPOSITORIES: GEO

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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

Characterization of chromatin accessibility changes in retinal ganglion cells (RGCs) following optic nerve crush

Project description:In this study, we profiled epigenetic and transcriptional landscapes in injured RGCs to identify transcription factors driving critical chromatin state and gene expression changes in reponse to injury.

2022-05-06 | GSE184547 | GEO

NMNAT2 Is Downregulated in Glaucomatous RGCs and RGC-Specific Gene Therapy with NMNAT2 Overexpression Rescues Glaucomatous Neurodegeneration and Visual Function

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

Characterization of chromatin accessibility changes in retinal ganglion cells (RGCs) following optic nerve crush

Project description:Characterization of chromatin accessibility changes in retinal ganglion cells (RGCs) following optic nerve crush

| PRJNA765016 | ENA

Displacement of PDE4D3 with an anchoring disruptor peptide is RGC protective after injury

Project description:Loss of retinal ganglion cells (RGCs) is central to the pathogenesis of optic neuropathies such as glaucoma. Increased cAMP signaling in RGCs is neuroprotective, as has been previously demonstrated in multiple animal models, including optic nerve crush (ONC) injury. We have shown that displacement of the cAMP-specific phosphodiesterase PDE4D3 from an RGC perinuclear compartment by expression of the modified PDE4D3 N-terminal peptide 4D3(E) increases perinuclear protein kinase A activity in cultured neurons and RGC survival in vivo after ONC injury. To explore potential mechanisms by which 4D3(E) expression promotes neuroprotection, mice intravitreally injected with an adeno-associated virus to express an mCherry-tagged 4D3(E) peptide were subjected to ONC injury and analyzed by single cell RNA-sequencing (scRNA-seq) for changes in RGC gene expression. 4D3(E)-mCherry expression was associated with an attenuation of injury-induced changes in gene expression, thereby supporting the hypothesis that enhanced perinuclear PKA signaling promotes neuroprotective RGC gene expression.

2024-08-28 | GSE260952 | GEO

Shtn1, a retinal ganglion cell (RGC) specific gene, regulates RGC neurite development: Insights from an RGC direct somatic cell reprogramming model

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

Single-cell trajectory analysis of the differentiation of RGCs in the VZ (scRNA-seq)

Project description:The largest germinal niche of the adult mammal brain locates at the ventricular zone (VZ), which is made up of adult neural stem cells (NSCs) and multiciliated ependymal cells (EPCs). Both NSCs and EPCs derive from radial glia (RG), whereas the transcriptomic dynamic changes of the cell fate continuum remain elusive. Here, we used single cell RNA-seq of CD133 positive RGCs from the VZ of new born mice to uncover the developmental trajectories of RGCs to NSCs and EPCs.

2024-04-21 | E-MTAB-13858 | biostudies-arrayexpress

Transcriptome analysis of Chrdl1-treated RGCs

Project description:Transcriptome analysis of Chrdl1-treated RGCs

| PRJNA427397 | ENA

Differential response of C57BL/6J mouse and DBA/2J mouse to optic nerve crush

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

Opioid receptor signaling suppresses leukemia by inducing TET-dependent DNA demethylation [RNA-seq]

Project description:Acute myeloid leukemia (AML) is a group of heterogeneous diseases with high malignancy. The ten-eleven translocation (TET) mediated DNA demethylation was known to be critically associated with AML pathogenesis. Through chemical compound screening, we found an opioid receptor agonist, namely loperamide hydrochloride (OPA1), most significantly suppressed AML cell viability. The potential therapeutic effects of opioid receptor agonists, especially OPA1, were then verified in AML cells in vitro, and AML mouse models carrying t(11q23) and t(8;21) in vivo. OPA1-induced activation of OPRM1 enhanced the transcription of TET2, increased DNA 5-hydroxymethylcytosine (5hmC) modification, and in turn, activated NFκB signaling. Notably, AML with TET2 mutations or chemotherapy resistance were sensitive to OPA1. Our results unveiled the previously unappreciated OPRM1-TET2-5hmC-TRAF2 regulatory axis in AML, and highlighted the therapeutic potential of opioid agonists, particularly OPA1, a FDA-approved antidiarrheal drug, in treating AML, especially TET2 mutated AML and chemotherapy-resistant AML, which were known to have poor prognosis.

2023-03-20 | GSE147510 | GEO

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