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Proliferation and neural stem cell potential of diencephalic astrocytes revealed by genome-wide expression is SMAd4 dependent – scRNA-seq

ABSTRACT: Neural stem cells (NSCs) have astroglial hallmarks, while astrocytes in the intact adult mammalian brain parenchyma are thought to be postmitotic and lack NSC hallmarks that are activated only after injury. Analysis of genome-wide expression at population and single cell level in astrocytes from the diencephalon (DIE) and the cerebral cortex Grey grey Matter matter (CTX GM) revealed cell cycle associated gene expression, that we verified in situ by PCNA immunostaining and incorporation of the thymidine analog EdU. Strikingly, clonal analysis using GLASTCreERT2/confetti mice showed that only diencephalic astrocytes give rise to daughter cells in multi-cellular clones. In addition, subsets of astrocytes only from the diencephalon form multipotent, self-renewing neurospheres in vitro. Given the differential expression levels of genes related to Smad mediated transcriptional regulation between CTX GM and DIE astrocytes, we deleted the common mediator Smad4 in adult astrocytes. This abrogates proliferation of diencephalic astrocytes in vivo and their neurosphere formation in vitro. This work therefore identified a novel astrocyte subtype with NSC hallmarks in the diencephalon and implicates ongoing astrocytogenesis as a region-specific hallmark in the adult brain.

ORGANISM(S): Mus musculus

PROVIDER: GSE149114 | GEO | 2021/09/01

REPOSITORIES: GEO

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Proliferation and neural stem cell potential of diencephalic astrocytes revealed by genome-wide expression is SMAd4 dependent – RNAseq

Project description:Neural stem cells (NSCs) have astroglial hallmarks, while astrocytes in the intact adult mammalian brain parenchyma are thought to be postmitotic and lack NSC hallmarks that are activated only after injury. Analysis of genome-wide expression at population and single cell level in astrocytes from the diencephalon (DIE) and the cerebral cortex Grey grey Matter matter (CTX GM) revealed cell cycle associated gene expression, that we verified in situ by PCNA immunostaining and incorporation of the thymidine analog EdU. Strikingly, clonal analysis using GLASTCreERT2/confetti mice showed that only diencephalic astrocytes give rise to daughter cells in multi-cellular clones. In addition, subsets of astrocytes only from the diencephalon form multipotent, self-renewing neurospheres in vitro. Given the differential expression levels of genes related to Smad mediated transcriptional regulation between CTX GM and DIE astrocytes, we deleted the common mediator Smad4 in adult astrocytes. This abrogates proliferation of diencephalic astrocytes in vivo and their neurosphere formation in vitro. This work therefore identified a novel astrocyte subtype with NSC hallmarks in the diencephalon and implicates ongoing astrocytogenesis as a region-specific hallmark in the adult brain.

2021-09-01 | GSE149112 | GEO

Diverse gene expression of diencephalon astrocytes reveals proliferation regulated by Smad4 - scRNA-seq II

Project description:Astrocytes are crucial for neural network function throughout the brain and also show region-specific gene expression differences. To explore this at the single cell level, we isolated cells by ACSA2 MACS from the diencephalon. Single cell RNA-seq revealed two super clusters of cells expressing astrocyte markers, one of which expressed many ependymal markers. Fluorescent labelling of ependymal cells allowed removing them during dissection. The remaining astrocytes and astrocyte-like cells show considerable heterogeneity with some subsets or gene expression states showing more wide-spread and others more restricted mapping of gene expression throughout the forebrain. Surprisingly, diencephalic astrocytes express proliferation regulating genes. Immunostaining for proiliferation markers, DNA-base incorporation and clonal analysis revealed ongoing low level astrocytogenesis even in 8 months old mice. Comparing gene expression of astrocytes in diencephalon and cortex grey matter identified Smad4 as a key regulator of astrocyte in vivo proliferation and in vitro neurosphere formation. Thus, astrocyte diversity is seemingly partitioned in wide-spread and region-specific subsets and reveals the novel concept of adult astrocytogenesis in the diencephalon in a Smad4-dependent manner.

2021-09-01 | GSE176456 | GEO

Gene expression of white and grey matter demyelinated areas and normal appearing matter from Multiple Sclerosis leukocortial lesions of human post-mortem tissue

Project description:Using laser capture microscopy, white (WM) and grey matter (GM) demyelinated areas and normal appearing matter was collected from histologically verified leukocortical lesions from snap-frozen human post mortem tissuederived from Multiple Sclerosis patients. Our data shows large differences in gene expression in WM and GM demyelinated areas (compared to their respective normal appearing matter) even when the demyelinated areas are spatially connected such as in leukocortical lesions. Thus, we show that WM demyelinated areas and GM demyelinated areas are distinct entities with distinct pathology. Therefore findings observed in WM demyelinated areas cannot be generalized to GM demyelinated areas.

2022-01-02 | GSE149326 | GEO

mRNA-seq analyses for the differentially expressed genes (DEGs) among Con, NF VM-astrocytes, Ctx-astrocytes, and control Ctx-NPCs

Project description:To gain further molecular insight into the observed astrocyte functions, we performed RNA-sequencing (RNA-seq) analysis of the differentiated Ctx-NPCs (control), Ctx-astrocytes and VM-astrocytes used in the co-culture and CM experiments. The genes that are differentially expressed (DEGs) in Ctx-astrocytes compared to differentiated Ctx-NPCs (FPKM>1, log2>1) significantly overlapped with DEGs in VM-astrocytes compared to differentiated Ctx-NPCs

2020-10-25 | GSE106216 | GEO

Analysis of splicing abnormalities in the white matter of myotonic dystrophy type 1 brain using RNA-sequence

Project description:Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by the genomic expansions of CTG repeats, in which RNA-binding proteins, such as muscleblind-like protein, are sequestered in the nucleus, and abnormal splicing is observed in various genes. Although abnormal splicing reportedly occurs in the brains of patients with DM1, it is relation to the central nervous system symptoms is unknown. Several imaging studies have indicated substantial white matter (WM) defects in patients with DM1. Here, we performed RNA-sequencing and analysis of CTG repeat lengths in the frontal lobe of patients with DM1, separating the grey matter (GM) and WM, to investigate the splicing abnormalities in the DM1 brain, especially in the WM. The results demonstrated the number of repeats in the GM tended to be increase, with several genes showing similar levels of splicing abnormalities in the GM and WM, suggesting that the WM defects in DM1 are not only caused by aberrant splicing of GM RNA but also of WM RNA, which could be attributed to abnormal splicing of glial cell RNAs.

2023-10-25 | GSE224437 | GEO

Multiple sclerosis cortical normal-appearing grey matter and grey matter lesions

Project description:Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the brain. Among characteristics of MS pathology are cortical grey matter abnormalities, which have been linked to clinical signs such as cognitive impairment. To understand MS cortical grey matter lesion pathogenesis, we performed differential gene expression analysis of MS cortical normal-appearing grey matter (NAGM) and grey matter lesions. HLA-DRB1 is the transcript with highest expression in MS NAGM with a bimodal distribution among the examined cases. Genotyping revealed that every case with the MS-associated HLA-DR15 haplotype also shows high HLA-DRB1 expression. Quantitative immunohistochemical analysis confirmed the higher expression of HLA-DRB1 in HLA-DRB1*15:01 cases at the protein level. Analysis of grey matter lesion size revealed a significant increase of cortical lesion size in cases with high HLA-DRB1 expression. Our data indicate that increased HLA-DRB1 expression in the brain of MS patients may be an important factor in how the HLA-DR15 haplotype contributes to MS risk in the target organ.

2020-01-13 | GSE131279 | GEO

Multiple sclerosis cortical normal-appearing grey matter and control grey matter

Project description:Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the brain. Among characteristics of MS pathology are cortical grey matter abnormalities, which have been linked to clinical signs such as cognitive impairment. To understand MS cortical grey matter pathogenesis, we performed differential gene expression analysis of MS normal appearing grey matter (NAGM) and control grey matter. HLA-DRB1 is the transcript with highest expression in MS NAGM with a bimodal distribution among the examined cases. Genotyping revealed that every case with the MS-associated HLA-DR15 haplotype also shows high HLA-DRB1 expression. Quantitative immunohistochemical analysis confirmed the higher expression of HLA-DRB1 in HLA-DRB1*15:01 cases at the protein level. Analysis of grey matter lesion size revealed a significant increase of cortical lesion size in cases with high HLA-DRB1 expression. Our data indicate that increased HLA-DRB1 expression in the brain of MS patients may be an important factor in how the HLA-DR15 haplotype contributes to MS risk in the target organ.

2020-01-13 | GSE131281 | GEO

RNAseq of human Multiple Sclerosis cortex with hnRNP A1 dysfunction

Project description:We sought to identify alterations in RNA expression and splicing in human grey matter from the brains of people with Multiple Sclerosis (MS) where we observe mislocalization of the RNA binding protein hnRNP A1. Thus, RNA was extracted from fresh-frozen post-mortem brain samples of three people with MS and compared to RNA extracted from fresh-frozen post-mortem brain samples of three healthy controls by RNAseq. Regions of interest in human grey matter were defined by immunostaining for hnRNP A1 to confirm grey matter regions with hnRNP A1 mislocalization in MS tissue, and grey matter regions with normal hnRNP A1 localization in control tissue, and the same region from an adjacent tissue section was dissected with a razor blade and used for RNA extraction and sequencing.

2024-01-04 | GSE207680 | GEO

Multiple sclerosis cortical normal-appearing grey matter, grey matter lesions, and control grey matter

Project description:Multiple sclerosis cortical normal-appearing grey matter, grey matter lesions, and control grey matter

| PRJNA543111 | ENA

Transcriptional profiling of human microglia reveals grey-white matter heterogeneity and multiple sclerosis-associated changes

Project description:Microglia are brain-resident, myelin-phagocytosing cells, yet their role in lesion initiation in grey and white matter regions in multiple sclerosis (MS) is unclear. We isolated primary microglia from both, occipital cortex and corpus callosum, of 10 MS and 11 control donors and studied their transcriptional profile by RNA sequencing, thereby identifying regional and MS-associated changes. Identification of pathways underlying regional differences showed a relatively increased type I interferon response in cortical grey matter microglia, while white matter microglia more highly expressed NF-κB pathway genes. In normal-appearing white matter MS tissue, lipid metabolism genes were increased, suggesting processing of myelin by microglia already in areas seemingly devoid of MS pathology. Normal-appearing grey matter MS microglia showed increased activation of glycolysis and metal ion homeostasis, possibly reflecting microglia reacting to iron depositions. Notably, expression of genes associated with microglia homeostasis were hardly changed, suggesting that subtle regional changes in MS-associated microglia do not yet affect their resting state.

2019-03-13 | GSE111972 | GEO

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