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M6A epitranscriptome regulates axonogenesis and reprogramming of retinal ganglion cells [RNA-seq]

ABSTRACT: induced retinal ganglion cells (iRGCs) is an excellent system to generate RGC-like neurons for translational and theoretical studies. N6-methyladenosine (m6A) is the most prevalent internal modification in mRNAs. Using this iRGC system, we demonstrated that Mettl3, the core component of the m6A-methyltransferase complex, promotes iRGC axon development and the final iRGC reprogramming outcome.

ORGANISM(S): Mus musculus

PROVIDER: GSE305554 | GEO | 2026/02/24

REPOSITORIES: GEO

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m6A epitranscriptome regulates axonogenesis and reprogramming of retinal ganglion cells

Project description:induced retinal ganglion cells (iRGCs) is an excellent system to generate RGC-like neurons for translational and theoretical studies. N6-methyladenosine (m6A) is the most prevalent internal modification in mRNAs. Using this iRGC system, we demonstrated that Mettl3, the core component of the m6A-methyltransferase complex, promotes iRGC axon development and the final iRGC reprogramming outcome.

2026-02-24 | GSE305553 | 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

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

The efficient induction of human retinal ganglion-like cells provides a platform for studying optic neuropathies

Project description:Retinal ganglion cells (RGCs) are essential for vision perception. In glaucoma and other optic neuropathies, RGCs and their optic axons undergo degenerative change and cell death; this can result in irreversible vision loss. Here we developed a rapid protocol for directly inducing RGC differentiation from human induced pluripotent stem cells (iPSCs) by the overexpression of ATOH7, BRN3B and SOX4. The hiPSC-derived RGC-like cells (iRGCs) show robust expression of various RGC-specific markers, such as BRN3A, EBF1, ISL1 and RBPMS. A functional assessment was also carried out and this demonstrated that these iRGCs display stimulus-induced neuronal activity, as well as spontaneous neuronal activity. Ethambutol (EMB), an effective first-line anti-tuberculosis agent, is known to cause serious visual impairment and irreversible vision loss due to the RGC degeneration in a significant number of treated patients. Using our iRGCs, EMB was found to induce significant dose-dependent and time-dependent increases in cell death and neurite degeneration. Western blot analysis revealed that the expression levels of p62 and LC3-II were upregulated, and further investigations revealed that EMB caused a blockade of lysosome-autophagosome fusion; this indicates that impairment of autophagic flux is one of the adverse effects of that EMB has on iRGCs. In addition, EMB was found to elevate intracellular reactive oxygen species (ROS) levels increasing apoptotic cell death. This could be partially rescued by the co-treatment with the ROS scavenger NAC. Taken together, our findings suggest that this iRGC model, which achieves both high yield and high purity, is suitable for investigating optic neuropathies, as well as being useful when searching for potential drugs for therapeutic treatment and/or disease prevention.

2023-08-04 | GSE236027 | GEO

Müller glia-mediated protection of retinal ganglion cells from ethambutol-induced neurotoxicity through brain-derived neurotrophic factor

Project description:Ethambutol (EMB)-associated optic neuropathy is the most common toxic optic neuropathy and poses a significant visual threat worldwide. This study aimed to investigate the neuroprotective roles of Müller glia, the most abundant macroglia in the retina, and their associated growth factors in supporting retinal ganglion cells (RGCs) under EMB-induced toxicity. Induced RGC-like cells (iRGCs), differentiated from human induced pluripotent stem cells, and Müller glial cell line MIO-M1 were used as cellular models. RNA sequencing revealed that EMB significantly disrupted neurotrophin and BDNF-associated pathways in iRGCs. Co-culture with MIO-M1 cells markedly enhanced the survival of iRGCs during EMB exposure. mRNA of BDNF and nerve growth factor (NGF) were elevated in MIO-M1 cells, while only BDNF improved the survival and morphological integrity of iRGCs under EMB treatment. Administration of BDNF also improved the survival of RGC in mouse retinal explants. The pro-survival effect of BDNF was suppressed by GNF5837, a pan-TRK inhibitor. Among the three downstream effectors of BDNF signaling, AKT was most prominently activated by BDNF in EMB-treated iRGCs, compared to ERK and PLCγ1. Furthermore, the protective effect of BDNF was blocked by the AKT inhibitor MK-2206 but not by the ERK inhibitor GDC-0094. Müller glia confer neuroprotection to RGCs under EMB-induced stress, primarily via BDNF signaling. AKT functions as the key downstream effector mediating this protective response. These findings suggest that the BDNF-AKT signaling may serve as a promising therapeutic target for EMB-associated optic neuropathy.

2025-12-03 | GSE294687 | GEO

m6A epitranscriptome regulates axonogenesis and reprogramming of retinal ganglion cells

Project description:m6A epitranscriptome regulates axonogenesis and reprogramming of retinal ganglion cells

| PRJNA1306501 | ENA

m6A epitranscriptome regulates axonogenesis and reprogramming of retinal ganglion cells [RNA-seq]

Project description:m6A epitranscriptome regulates axonogenesis and reprogramming of retinal ganglion cells [RNA-seq]

| PRJNA1306497 | ENA

A cis-regulatory module underlies retinal ganglion cell genesis and axonogenesis [Set1.Sc-ATAC-Seq retina E14.5 WT retina]

Project description:During retinogenesis, the proneural bHLH transcription factor Atoh7 is transiently expressed in retinal progenitor cells (RPCs) and is required for retinal ganglion cell (RGC) differentiation. In humans, a deletion in a distal non-coding regulatory region upstream of ATOH7 is associated with nonsyndromic congenital retinal nonattachment (NCRNA) disorder, characterized by optic nerve atrophy and complete blindness. Here we functionally interrogate the significance of the Atoh7 enhancer landscape to retinogenesis. We demonstrate that deletion of the enhancer structure upstream of Atoh7 in mice leads to RGC deficiency, optic nerve hypoplasia and blood vascular abnormalities, phenocopying inactivation of Atoh7 and recapitulating key features of NCRNA. We further provide evidence that the loss of the Atoh7 remote enhancer impacts ipsilaterally-projecting RGCs and disrupts proper axonal projections to the brain targets. Transcriptionally, deletion of the Atoh7 remote enhancer is associated with dysregulation of axonogenesis genes, including the derepression of the axon repulsive cue Robo3 which is normally epigenetically silenced in the developing retina. Our data provide novel insights into how Atoh7 enhancer elements function to promote RGC development and optic nerve formation and uncover a key role of Atoh7 in the transcriptional control of axon guidance molecules possibly via epigenetic mechanisms.

2024-06-06 | GSE245538 | GEO

Direct induction of retinal ganglion cell-like neurons

Project description:Retinal ganglion cells (RGCs) are the projection neurons in the retina that connect the visual sensing tissue to the brain. We found that Ascl1/Brn3b/Isl1 transcription factor combination can quickly and efficiently reprogramming mouse embryonic fibroblasts (MEFs) into retinal ganglion cell-like neurons (iRGCs). Using RNA-seq, we analyzed the transcriptomes of MEFs infected with Ascl1/Brn3b/Isl1-overexpressing viruses on day 2 or day 7 of reprogramming, or the final iRGCs on day 13 of reprogramming.

2020-09-30 | GSE140689 | GEO

Placental epitranscriptome-wide analysis of revealed the m6A modification level at 5’ UTR related fetal growth

Project description:To further understand the relationship between the level of gene expression and protein translation in human placenta, we focused on N6-methyladenosine: m6A, which is a methylation modification of mRNA acting as a post-transcriptional regulation which has drawn attention in recent years. It is said that m6A affects the fate of mRNA. In addition, it is thought that m6A affects gene expression in the placenta of preeclampsia which is a representative disease of perinatal period and fetal growth abnormality, and the placentas of children who were small for date (SFD) or heavy for date (HFD) were studied in addition to appropriate for date (AFD) preganancies. The SFD placentas contained half of the cases with PE. HEK293T cell was used to confirm the experimental system. PolyA RNA was purified from each tissue and cell, and libraries were prepared from immunoprecipitated (IP) samples using anti-m6A antibody and input samples, and sequenced with Hiseq 1500/2500 and RNAseq was carried out.

2019-10-10 | E-MTAB-6507 | biostudies-arrayexpress

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