Ptbp1 deletion does not induce glia-to-neuron conversion in adult mouse retina and brain.
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ABSTRACT:
PROVIDER: PRJNA767059 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: scRNA-Seq was performed to profile changes in adult retina Muller glia cells and brain astrocytes after Ptbp1 deletion
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Project description:Loss of neurons in the neural retina is a leading cause of vision loss. Retinal regeneration in zebrafish is attributed to Müller glia, which are activated, adopt a stem cell-like state, proliferate, and generate new neurons. Despite the same endogenous Müller glia being present in all vertebrates including humans, Müller glia activation in mammals leads to glial scarring instead of neurogenesis. Therefore, understanding Müller glia cellular states and molecular processes during zebrafish regeneration may allow us to improve mammalian regeneration. Since only a subset of Müller glia activate following neuron loss, we asked whether a specialised subset of Müller glia might be genetically primed for activation. Single-cell RNA sequencing (sc-RNAseq) from integrated zebrafish Müller glia samples reveals heterogeneity of gene expression across the quiescent Müller glia pool with 4 main clusters emerging, two of which are genetically similar. Labelling for key differentially expressed markers identified that these main clusters correlated with glia spatially distributed across dorsal, central and ventral retina. Using a genetically driven, chemically induced nitroreductase approach, three distinct photoreceptor types were ablated: the long (Lws2), short wavelength-sensitive (Sws2) and rod (Xops) photoreceptors, which also differ in their abundance. As expected, histological analysis of the three injuries and sc-RNAseq data for the two cone photoreceptor ablations identified common genetic program involved in the transition of Müller glia quiescence to activation, and differential responses to injury related to either injury extent or subtype of photoreceptor targeted. Interestingly, despite differences in the distributed across the retina, biased activation of Müller glia was observed in dorsal and central regions. Gene ontology analysis revealed that these injury-responsive dorsal and central Müller glia express genes related to dorsal/ventral pattern formation, growth factor activity, and regulation of developmental process. Müller glia upregulated genes related to homeostasis as well as certain AP-1 and injury-responsive transcription factors, followed by expression of genes involved in cell cycle, chromatin remodeling, and microtubule organisation. Prior to cell cycle entry, Müller glia show a transient upregulation of genes involved in gliogenesis, and Notch signalling. These findings enhance our understanding of heterogeneous states of quiescent Müller glia, and how these differences relate to activation and regeneration potential following neural ablation. A comparison of the distinct quiescent Müller glia with glia states in mammals will reveal key molecular pathways that could be targeted for improved mammalian neural regeneration.
2023-08-21 | GSE218107 | GEO
Project description:Alzheimer’s Disease (AD) pathogenesis is thought to begin up to 20 years before cognitive symptoms appear, suggesting the need for more sensitive diagnostic biomarkers of AD. In this report, we demonstrated pathological changes in retinal Müller glia significantly earlier than amyloid pathology in AD mouse models. By utilizing the knock-in NLGF mouse model, we surprisingly discovered an increase in reticulon 3 (RTN3) protein levels in the NLGF retina as early as postnatal day 30 (P30). Despite RTN3 being a canonically neuronal protein, this increase was noted in the retinal Müller glia, confirmed by immunohistochemical characterization. Further unbiased transcriptomic assays of the P30 NLGF retina revealed that retinal Müller glia were the most sensitive responding cells in this mouse retina, compared to other cell types including photoreceptor cells and ganglion neurons. Pathway analyses of differentially expressed genes in glia cells showed activation of ER stress response via the upregulation of unfolded protein response (UPR) proteins such as ATF4 and CHOP. Early elevation of RTN3 in response to challenges by toxic Aβ likely facilitated UPR. Altogether, these findings suggest that Müller glia act as a sentinel for AD pathology in the retina and should aid for both intervention and diagnosis.
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Project description:This study has applied proteomic methodologies to compare protein expression profiles of gliotic and normal human retina as well as established human Müller stem cell lines. It is hoped that this investigation may provide insight into mechanisms of gliosis and also aid studies focusing on endogenous regeneration of the retina following disease or injury
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Project description:Linking YAP to Müller glia quiescence exit in the degenerative retina
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Project description:Parkinson’s disease (PD) is a multifactorial disease caused by irreversible progressive loss of dopaminergic neurons. Recent studies reported successful conversion of astrocytes into dopaminergic neurons by repressing polypyrimidine tract binding protein 1 (PTBP1), which led to a rescue of motor symptoms in a mouse model for PD. However, the mechanisms underlying this cell type conversion remain underexplored and controversial. Here, we devised a strategy using adenine base editing to effectively knockdown PTBP1 in astrocytes and neurons in a PD mouse model. Using AAV delivery vectors at a dose of 2´108 vg per animal, we found that Ptbp1 editing in neurons, but not astrocytes, of the substantia nigra pars compacta and striatum resulted in the formation of tyrosine hydroxylase (TH)+ cells and the rescue of forelimb akinesia and spontaneous rotations. Phenotypic analysis of TH+ cells indicates that they originated from non-dividing neurons and acquired dopaminergic neuronal markers upon PTBP1 downregulation. While further research is required to fully understand the origin, identity, and function of these newly generated TH+ cells, our study reveals that the downregulation of PTBP1 can reprogram neurons to mitigate symptoms in PD mice.
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Project description:We describe an improved individual nucleotide resolution CLIP protocol (iiCLIP), which can be completed within 4 days from UV crosslinking to libraries for sequencing. For benchmarking, we directly compared PTBP1 iiCLIP libraries with the iCLIP2 protocol produced under standardised conditions with 1 million HEK293 cells, and with public eCLIP and iCLIP PTBP1 data. There are 3 PTBP1 iiCLIP libraries, 1 input iiCLIP library and 1 PTBP1 iCLIP2 library produced in this study.
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