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Single Cell Transcriptome Analysis of Regenerating RGCs Reveals Potent Glaucoma Neural Repair Genes [First_batch_reg_RGCs]

ABSTRACT: Axon regeneration holds great promise for neural repair of CNS axonopathies, including glaucoma. Pten deletion in retinal ganglion cell (RGC) promotes potent optic nerve regeneration, but only a small population of Pten-null RGCs are actually regenerating RGCs (regRGCs); most surviving RGCs (surRGCs) remain non-regenerative. Here we developed a strategy to specifically label and purify regRGCs and surRGCs respectively from the same Pten deletion mice after optic nerve crush, in which they differ only in their regeneration capability. Smart-Seq2 single cell transcriptome analysis revealed novel regeneration-associated genes that significantly promote axon regeneration. The most potent of these, Anxa2, acts synergistically with its ligand tPA in Pten deletion-induced axon regeneration. Anxa2, its downstream effector ILK, and Mpp1 dramatically protect RGC somata and axons and preserves visual function in a clinically relevant model of glaucoma, demonstrating the exciting potential of this innovative strategy to identify novel effective neural repair candidates.

ORGANISM(S): Mus musculus

PROVIDER: GSE206622 | GEO | 2022/08/20

REPOSITORIES: GEO

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Single Cell Transcriptome Analysis of Regenerating RGCs Reveals Potent Glaucoma Neural Repair Genes [Second_batch_sur_RGCs]

Project description:Axon regeneration holds great promise for neural repair of CNS axonopathies, including glaucoma. Pten deletion in retinal ganglion cell (RGC) promotes potent optic nerve regeneration, but only a small population of Pten-null RGCs are actually regenerating RGCs (regRGCs); most surviving RGCs (surRGCs) remain non-regenerative. Here we developed a strategy to specifically label and purify regRGCs and surRGCs respectively from the same Pten deletion mice after optic nerve crush, in which they differ only in their regeneration capability. Smart-Seq2 single cell transcriptome analysis revealed novel regeneration-associated genes that significantly promote axon regeneration. The most potent of these, Anxa2, acts synergistically with its ligand tPA in Pten deletion-induced axon regeneration. Anxa2, its downstream effector ILK, and Mpp1 dramatically protect RGC somata and axons and preserves visual function in a clinically relevant model of glaucoma, demonstrating the exciting potential of this innovative strategy to identify novel effective neural repair candidates.

2022-08-20 | GSE206625 | GEO

Single Cell Transcriptome Analysis of Regenerating RGCs Reveals Potent Glaucoma Neural Repair Genes [Second_batch_reg_RGCs]

2022-08-20 | GSE206624 | GEO

Single Cell Transcriptome Analysis of Regenerating RGCs Reveals Potent Glaucoma Neural Repair Genes [First_batch_sur_RGCs]

2022-08-20 | GSE206623 | GEO

MicroRNA-19a-PTEN axis is involved in the developmental decline of axon regenerative capacity in retinal ganglion cells

Project description:Irreversible blindness from glaucoma and optic neuropathies is attributed to retinal ganglion cells (RGCs) losing the ability to regenerate axons. While several transcription factors and proteins have demonstrated enhancement of axon regeneration after optic nerve injury, mechanisms contributing to the age-related decline in axon regenerative capacity remains elusive. Here, we show that microRNAs are differentially expressed during RGC development, and identify microRNA-19a (miR-19a) as a heterochronic marker; developmental decline of miR-19a relieves suppression of PTEN, a key regulator of axon regeneration, and serves as a temporal indicator of decreasing axon regenerative capacity. Intravitreal injection of miR-19a promotes axon regeneration after optic nerve crush in adult mice, and increases axon extension in RGCs isolated from aged human donors. This uncovers a previously unrecognized involvement of the miR-19a-PTEN axis in RGC axon regeneration, and demonstrates therapeutic potential of microRNA-mediated restoration of axon regenerative capacity via intravitreal injection in patients with optic neuropathies.

2020-07-04 | GSE102458 | 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

Sox11 expression in adult retina promotes regeneration of some ganglion cell types but kills others

Project description:At least 30 types of retinal ganglion cell (RGC) send distinct messages through the optic nerve to the brain. Strategies for promoting regeneration of RGC axons following injury act on only some of these types. Here we tested the hypothesis that over-expressing developmentally important transcription factors in adult RGCs could reprogram them to a “youthful” growth-competent state and promote regeneration of other types. From a screen of transcription factors expressed by developing RGCs, we found one, Sox11, that induced substantial axon regeneration. Transcriptome profiling confirmed that Sox11 activates genes involved in cytoskeletal remodeling and axon growth. Remarkably, alpha-RGCs, which preferentially regenerate following treatments such as PTEN deletion, were killed by Sox 11. Thus, Sox 11 promotes regeneration of non-alpha RGCs, which are refractory to PTEN. We conclude that Sox11 can reprogram adult RGCs to a growth-competent state and that different growth-promoting interventions act on distinct neuronal types.

2017-06-25 | GSE87046 | GEO

Global gene expression changes in rat retinal ganglion cells after experimental glaucoma

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

Genome wide chromatin accessibility analysis reveals a role for CREB in retinal ganglion cells axon growth decline in development and regeneration after optic nerve injury [RNA-seq]

Project description:CNS neurons lose their ability to grow and regenerate axons during development. This is the case for Retinal Ganglion Cells (RGCs) in the retina, which transmit visual information to the brain via axons projecting into the optic nerve. RGCs are unable to regenerate their axon after injury, and start a degeneration process that leads to cell death and loss of vision. To identifying molecular mechanisms that increase regeneration of RGC and may offer new treatment strategies for patients with glaucoma or other types of optic neuropathies, we focused on the identification of transcription factors and chromatin accessible sites that are enriched in RGC during developmental stages, in which axon growth capacity is robust. We find that stage-specific gene expression changes are correlated with temporal changes in promoter chromatin accessibility. We also find that Creb binding motifs are enriched in the differentially opened regions of the chromatin at embryonic developmental stage. Overexpression of active Creb promotes axon regeneration after optic nerve injury. Our results provide a map of the chromatin accessibility during RGC development and highlights that manipulating TF associated with developmental stages can stimulate axon growth in adulthood.

2021-07-28 | GSE163563 | GEO

Genome wide chromatin accessibility analysis reveals a role for CREB in retinal ganglion cells axon growth decline in development and regeneration after optic nerve injury [ATAC-seq]

2021-07-28 | GSE163562 | GEO

Post-translational modification of Sox11 regulates RGC survival and axon regeneration

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

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