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Robust reprogramming of glia into neurons by inhibition of Notch signaling and NFI factors in adult mammalian retina.

ABSTRACT: scRNA-Seq was performed on adult control and Rbpj-deleted mouse retinas to profile changes in gene expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE246574 | GEO | 2023/11/03

REPOSITORIES: GEO

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Robust reprogramming of glia into neurons by inhibition of Notch signaling and nuclear factor I (NFI) factors in adult mammalian retina.

Project description:Generation of neurons through direct reprogramming has emerged as a promising therapeutic approach for treating neurodegenerative diseases. In this study, we present an efficient method for reprogramming retinal glial cells into neurons. By suppressing Notch signaling by disrupting either Rbpj or Notch1/2, we induced mature Müller glial cells to reprogram into bipolar- and amacrine-like neurons. We demonstrate that Rbpj directly activates both Notch effector genes and genes specific to mature Müller glia while indirectly repressing expression of neurogenic basic helix-loop-helix (bHLH) factors. Combined loss of function of Rbpj and Nfia/b/x resulted in conversion of nearly all Müller glia to neurons. Last, inducing Müller glial proliferation by overexpression of dominant-active Yap promotes neurogenesis in both Rbpj- and Nfia/b/x/Rbpj-deficient Müller glia. These findings demonstrate that Notch signaling and NFI factors act in parallel to inhibit neurogenic competence in mammalian Müller glia and help clarify potential strategies for regenerative therapies aimed at treating retinal dystrophies.

| S-EPMC11244444 | biostudies-literature

Oct4 overexpression and suppression of Notch signaling synergistically induce neurogenic competence in mammalian Muller glia.

Project description:scRNA-Seq and scMultiome (snRNA/ATAC) were performed on GFP+ cells from adult control and Rbpj-deleted mouse retinas with Gfap-Oct4 and Gfap-mCherry to profile changes in gene expression and chromatin accessibility

2024-09-25 | GSE277390 | GEO

Robust reprogramming of glia into neurons by inhibition of Notch signaling and NFI factors in adult mammalian retina.

Project description:Robust reprogramming of glia into neurons by inhibition of Notch signaling and NFI factors in adult mammalian retina.

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Melanopsin retinal ganglion cells regulate cone photoreceptor positioning in the mouse retina

Project description:We performed RNA sequencing on melanopsin deleted retinas (Opn4-DTA/DTA) to determine potential cues involved in instructing cone photoreceptor positioning

2018-05-22 | GSE112404 | GEO

Simultaneous cyclin D1 overexpression and p27kip1 knockdown enable robust Müller glia cell cycle reactivation in uninjured mouse retina

Project description:Müller glia (MG) stem cells are dormant retinal stem cells. While teleost fish MG re-enter the cell cycle after retinal damage and regenerate lost retinal neurons through asymmetric cell division of MG-derived progenitors, mammalian MG lack such ability. Here, we show that forced p27 downregulation and Cyclin D1 overexpression in MG using a single adeno-associated virus cell cycle activator (CCA) vector had a strong synergistic effect to induce MG proliferation. We used transcriptome profiling at single-cell level to demonstrate that CCA could induce MG proliferation and reprogram MG into neurogenic and rod-like cells. In addition, retinal injury combined with histone deacetylase inhibitor facilitates CCA to induce more rod-like cells, but not new cell types. Our study suggests new and powerful strategies for awakening the proliferative and neurogenic potential of MG in adult mammalian retinas.

2024-08-01 | GSE225142 | GEO

FBXO42 facilitates Notch signaling activation and global chromatin relaxation by promoting K63-linked polyubiquitination of RBPJ

Project description:Dysregulation of the Notch-RBPJ signaling pathway has been found associated with various human diseases including cancers; however, precisely how this key signaling pathway is fine-tuned via its interactors and modifications is still largely unknown. In this study, using a proteomic approach, we identified FBXO42 as a novel RBPJ interactor. FBXO42 promotes RBPJ polyubiquitination on lysine (K) 175 via K63 linkage, which enhances the association of RBPJ with chromatin remodeling complexes and induces a global chromatin relaxation. Genetically depleting FBXO42 or pharmacologically targeting its E3 ligase activity attenuates the Notch signaling-related leukemia development in vivo. Taken together, our findings not only revealed FBXO42 as a critical regulator of the Notch pathway by modulating RBPJ-dependent global chromatin landscape changes, but also provide insights into the therapeutic intervention of the Notch pathway for leukemia treatment.

2022-10-13 | PXD034938 | Pride

RBPJ/CBF1 interacts with L3MBTL3/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A/LSD1

Project description:Notch signaling is an evolutionarily conserved signal transduction pathway that is essential for metazoan development. At the molecular level, the key components of the Notch pathway are the NOTCH-family receptors, the ligands of the DSL (Delta, Serrate, Lag-2) family and the transcription factor CSL [CBF1/RBPJ, Su(H), Lag-1]. Upon ligand binding, the NOTCH Intra-Cellular Domain (NOTCH ICD) translocates into the nucleus and forms a complex with RBPJ to activate the transcription of target genes. In the absence of NOTCH ICD, RBPJ acts as a transcriptional repressor. Using a proteomic approach, we identified L3MBTL3 as a novel interactor of RBPJ. We discovered that L3MBTL3 competes with NOTCH ICD for binding to RBPJ. In the absence of NOTCH ICD, RBPJ recruits L3MBTL3 and its co-factor KDM1A [lysine (K)-specific demethylase 1A] to the promoters/enhancers of Notch target genes to promote H3K4me2 demethylation and transcriptional repression. In three distinct cell contexts in which Notch signaling governs cell fate, i.e., mature T-cells as well as brain and breast tumor cells, the loss of L3MBTL3 results in the de-repression of Notch target genes. Finally, the genetic analyses of the homologs of RBPJ and L3MBTL3 in Drosophila melanogaster and Caenorhabditis elegans demonstrate that the functional link between RBPJ/Su(H)/lag-1 and L3MBTL3/dL(3)mbt/lin-61 is evolutionarily conserved, thus identifying L3MBTL3 as a universal modulator of Notch signaling in metazoans.

2017-10-17 | PXD004196 | Pride

Photobiomodulation therapy activates YAP and triggers proliferation and dedifferentiation of Muller glia in mammalian retina.

Project description:Photobiomodulation therapy has been proposed as a promising therapeutic approach for retinal degenerative diseases. However, its effect on the regenerative capacity in mammalian retina and its intracellular signalling mechanisms remain unknown. Here, we show that photobiomodulation with 670 nm light stimulates Müller glia cell cycle re-entry and dedifferentiation into a progenitor-like state in both the uninjured and injured retina. We also find that 670 nm light treatment inhibits the Hippo pathway, which is activated in Müller glia following NaIO3-induced retinal injury. YAP, a major downstream effector of the Hippo signalling pathway was translocated into the nucleus of Müller glia along with YAP dephosphorylation in retina treated with 670 nm light. Deficiency of YAP attenuated Müller glia cell cycle re-entry and dedifferentiation. Our data reveal that the Hippo-YAP signalling pathway is associated with the photostimulatory effect on regenerative response in mammalian retina, and suggest a potential therapeutic strategy for retinal degenerative diseases. [BMB Reports 2023; 56(9): 502-507].

| S-EPMC10547971 | biostudies-literature

NFkB-signaling promotes glial reactivity and suppresses Muller glia-mediated neuron regeneration in the mammalian retina.

Project description:Müller glia (MG) in mammalian retinas are incapable of regenerating neurons after damage, whereas the MG in lower vertebrates regenerate functional neurons. Identification of cell signaling pathways and gene regulatory networks that regulate MG-mediated regeneration is key to harnessing the regenerative potential of MG. Here, we study how NFkB-signaling influences glial responses to damage and reprogramming of MG into neurons in the rodent retina. We find activation of NFkB and dynamic expression of NFkB-associated genes in MG after damage, however damage-induced NFkB activation is inhibited by microglia ablation. Knockout of NFkB in MG suppressed the accumulation of immune cells after damage. Inhibition of NFkB following NMDA-damage significantly enhanced the reprogramming of Ascl1-overexpressing MG into neuron-like cells. scRNA-seq of retinal glia following inhibition of NFkB reveals coordination with signaling via TGFβ2 and suppression of NFI and Id transcription factors. Inhibition of Smad3 signal transducer or Id transcription factors increased numbers of neuron-like cells produced by Ascl1-overexpressing MG. We conclude that NFkB is a key signaling hub that is activated in MG after damage, mediates the accumulation of immune cells, and suppresses the neurogenic potential of MG.

| S-EPMC9585486 | biostudies-literature

The regeneration-responsive careg element monitors activation of Müller glia after MNU-induced damage in the zebrafish retina

Project description:We found that the zebrafish non-coding element careg, which is induced in regenerating fins and heart, also participates in retina regeneration. Its activation persisted mostly in Müller glia from the onset to the termination of retina restoration. To assess the involvement of the careg:EGFP reporter during retina regeneration, we used a chemical injury model with MNU treatment. To identify the molecular profile of these cells, we performed a single-cell RNA sequencing (scRNA-seq) experiment of retinas dissected from adult careg:EGFP zebrafish at 3, 7, and 10 dpMNU. Our control retinas were dissected from fish at 3 days after treatment with heat-inactivated MNU

2023-05-10 | GSE202212 | GEO

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