Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

ER-targeted Bcl2 reactivates developmental programs to promote survival and axon regeneration of adult retinal ganglion cells

ABSTRACT: Axon regeneration in retinal ganglion cells (RGCs) holds great promise for reestablishing retina-to-brain connectivity and restoring visual function in RGC-related disorders such as glaucoma. However, the severely limited survival and regenerative capacity of adult RGCs following injury remain major impediments to effective neural repair. Bcl2 is a key regulator of neuronal survival and axon growth during development, yet its regenerative efficacy declines with maturation. Here, we investigated the reparative potential of Bcl2 from developmental and subcellular localization perspectives. We found that ER-targeted Bcl2 (ER-Bcl2), but not wild-type or mitochondria-targeted Bcl2, robustly promoted adult RGC survival and axon regeneration. Transcriptomic analyses combined with functional screening revealed that ER-Bcl2 reactivated developmentally downregulated genes, with Ikzf1 and Ikzf3 promoting neuronal survival and Stk17b driving axon regeneration. Moreover, ER-Bcl2 synergized with additional pro-regenerative cue to sustain neuronal survival and promote long-distance axon regeneration. Collectively, these findings identify ER-Bcl2 as a promising therapeutic strategy for enhancing neural repair and vision restoration.

ORGANISM(S): Mus musculus

PROVIDER: GSE345080 | GEO | 2026/08/26

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Experimental gene expression of developmentally downregulated Crmp1, Crmp4, and Crmp5 promotes axon regeneration and retinal ganglion cell survival after optic nerve injury [third-party re-analysis]

Project description:Collapsin response mediator proteins (Crmps) play roles in neuronal development and axon growth. However, neuronal-specific roles of Crmp1, Crmp4, and Crmp5 in regeneration of injured central nervous system (CNS) axons in vivo are unclear. Here, we analyzed developmental and subtype-specific expression of Crmp genes in retinal ganglion cells (RGCs), tested whether overexpressing Crmp1, Crmp4, or Crmp5 in RGCs through localized intralocular AAV2 delivery promotes axon regeneration after optic nerve injury in vivo, and characterized developmental co-regulation of gene-concept networks associated with Crmps. We found that all Crmp genes are developmentally downregulated in RGCs during maturation. However, while Crmp1, Crmp2, and Crmp4 were expressed to a varying degree in most RGC subtypes, Crmp3 and Crmp5 were expressed only in a small subset of RGC subtypes. We then found that after optic nerve injury, Crmp1, Crmp4, and Crmp5 promote RGC axon regeneration to varying extents, with Crmp4 promoting the most axon regeneration and also localizing to axons. We also found that Crmp1 and Crmp4, but not Crmp5, promote RGC survival. Finally, we found that Crmp1, Crmp2, Crmp4, and Crmp5's ability to promote axon regeneration is associated with neurodevelopmental mechanisms, which control RGC’s intrinsic axon growth capacity.

2023-04-10 | GSE228486 | GEO

Experimental gene expression of developmentally downregulated Crmp1, Crmp4, and Crmp5 promotes axon regeneration and retinal ganglion cell survival after optic nerve injury [bulk RNA-seq]

2023-04-10 | GSE228485 | 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

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

Nuclear-localized HDAC4 promotes neuroprotection of retinal ganglion cells after optic nerve injury

Project description:Background: As the sole output neurons for the retina, retinal ganglion cells (RGCs) transmit all visual information from the retina via the optic nerve to the brain. RGCs do not regenerate when injured, and effective therapies for promoting RGC survival and axon regeneration in optic neuropathies comprise an unmet clinical need, including in the common disease glaucoma. Histone deacetylases (HDACs) are epigenetic modifiers that repress gene transcription and play a key role in retinal development and disease. In this study, we identify the role of HDAC4 in RGC neurodegeneration and axon regeneration. Methods: The role of HDAC4 in the regulation of RGC neuroprotection and axon regeneration was studied in the mouse optic nerve crush (ONC) model for optic neuropathy by transduction of RGCs in vivo with adeno-associated virus (AAV) vectors. HDAC4- and ONC-dependent gene expression in vivo were studied by single cell RNA sequencing (scRNA-seq) of isolated RGCs. Results: A loss-of-function screen for the role of HDACs in RGC survival after optic nerve crush (ONC) injury identified HDAC4 as essential element for RGC survival. Accordingly, expression of a constitutively nuclear HDAC4 S246/467/632A missense mutant (3SA) increased RGC survival and axon regeneration after ONC injury. Similar beneficial effects were conferred by expression of an N-terminal fragment of HDAC4 (HDAC4 NT) that constitutively represses gene expression. scRNA-seq showed that one day after ONC injury, transcriptomic profiles of RGCs were altered such that HDAC4 NT and to a lesser degree the HDAC4 3SA mutant attenuated the gene expression changes associated with injury. Conclusions: This study demonstrates that enhancement of nuclear HDAC4 activity will promote RGC survival and axon regeneration in the ONC model of RGC injury, identifying HDAC4 as a novel target in the development of therapeutics for RGC protection and restoration of visual function.

2026-01-01 | GSE252860 | GEO

Single Cell Transcriptome Analysis of Regenerating RGCs Reveals Potent Glaucoma Neural Repair Genes [Second_batch_reg_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 | GSE206624 | GEO

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

2022-08-20 | GSE206623 | GEO

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

2022-08-20 | GSE206622 | GEO

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

2022-08-20 | GSE206625 | 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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data