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Molecular diversity of diencephalic astrocytes reveals adult astrogenesis regulated by Smad4.

ABSTRACT: Astrocytes regulate brain-wide functions and also show region-specific differences, but little is known about how general and region-specific functions are aligned at the single-cell level. To explore this, we isolated adult mouse diencephalic astrocytes by ACSA-2-mediated magnetic-activated cell sorting (MACS). Single-cell RNA-seq revealed 7 gene expression clusters of astrocytes, with 4 forming a supercluster. Within the supercluster, cells differed by gene expression related to ion homeostasis or metabolism, with the former sharing gene expression with other regions and the latter being restricted to specific regions. All clusters showed expression of proliferation-related genes, and proliferation of diencephalic astrocytes was confirmed by immunostaining. Clonal analysis demonstrated low level of astrogenesis in the adult diencephalon, but not in cerebral cortex grey matter. This led to the identification of Smad4 as a key regulator of diencephalic astrocyte in vivo proliferation and in vitro neurosphere formation. Thus, astrocytes show diverse gene expression states related to distinct functions with some subsets being more widespread while others are more regionally restricted. However, all share low-level proliferation revealing the novel concept of adult astrogenesis in the diencephalon.

SUBMITTER: Ohlig S

PROVIDER: S-EPMC8561644 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Molecular diversity of diencephalic astrocytes reveals adult astrogenesis regulated by Smad4

Project description:Astrocytes regulate brain-wide functions and also show region-specific differences, but little is known about how general and region-specific functions are aligned at the single cell level. To explore this, we isolated adult mouse diencephalic astrocytes by ACSA2-mediated magnetic-activated cell sorting (MACS). Single cell RNA-seq revealed 7 gene expression clusters of astrocytes, with 4 forming a super cluster. Within the super cluster, cells differed by gene expression related to ion homeostasis or metabolism, with the former sharing gene expression with other regions and the latter being restricted to specific regions. All clusters showed expression of proliferation related genes, and proliferation of diencephalic astrocytes was confirmed by immunostaining. Clonal analysis demonstrated low level of astrogenesis in the adult diencephalon, but not in cortex Grey Matter. This led to the identification of Smad4 as a key regulator of diencephalic astrocyte in vivo proliferation and in vitro neurosphere formation. Thus, astrocytes show diverse gene expression states related to distinct functions with some subsets being more wide-spread while others are more regionally restricted. However, all share low level proliferation revealing the novel concept of adult astrogenesis in the diencephalon.

| S-SCDT-EMBOJ-2020-107532 | biostudies-other

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-09-01 | GSE149115 | 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

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

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

2021-09-01 | GSE149114 | GEO

Comparison of larval and adult Drosophila astrocytes reveals stage-specific gene expression profiles.

Project description:The analysis of adult astrocyte glial cells has revealed a remarkable heterogeneity with regard to morphology, molecular signature, and physiology. A key question in glial biology is how such heterogeneity arises during brain development. One approach to this question is to identify genes with differential astrocyte expression during development; certain genes expressed later in neural development may contribute to astrocyte differentiation. We have utilized the Drosophila model and Translating Ribosome Affinity Purification (TRAP)-RNA-seq methods to derive the genome-wide expression profile of Drosophila larval astrocyte-like cells (hereafter referred to as astrocytes) for the first time. These studies identified hundreds of larval astrocyte-enriched genes that encode proteins important for metabolism, energy production, and protein synthesis, consistent with the known role of astrocytes in the metabolic support of neurons. Comparison of the larval profile with that observed for adults has identified genes with astrocyte-enriched expression specific to adulthood. These include genes important for metabolism and energy production, translation, chromatin modification, protein glycosylation, neuropeptide signaling, immune responses, vesicle-mediated trafficking or secretion, and the regulation of behavior. Among these functional classes, the expression of genes important for chromatin modification and vesicle-mediated trafficking or secretion is overrepresented in adult astrocytes based on Gene Ontology analysis. Certain genes with selective adult enrichment may mediate functions specific to this stage or may be important for the differentiation or maintenance of adult astrocytes, with the latter perhaps contributing to population heterogeneity.

| S-EPMC4390571 | biostudies-literature

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

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

| PRJNA736322 | ENA

Transient prenatal ruxolitinib treatment suppresses astrogenesis during development and improves learning and memory in adult mice.

Project description:Ruxolitinib is the first janus kinase 1 (JAK1) and JAK2 inhibitor that was approved by the United States Food and Drug Administration (FDA) agency for the treatment of myeloproliferative neoplasms. The drug targets the JAK/STAT signalling pathway, which is critical in regulating the gliogenesis process during nervous system development. In the study, we assessed the effect of non-maternal toxic dosages of ruxolitinib (0-30 mg/kg/day between E7.5-E20.5) on the brain of the developing mouse embryos. While the pregnant mice did not show any apparent adverse effects, the Gfap protein marker for glial cells and S100β mRNA marker for astrocytes were reduced in the postnatal day (P) 1.5 pups' brains. Gfap expression and Gfap+ cells were also suppressed in the differentiating neurospheres culture treated with ruxolitinib. Compared to the control group, adult mice treated with ruxolitinib prenatally showed no changes in motor coordination, locomotor function, and recognition memory. However, increased explorative behaviour within an open field and improved spatial learning and long-term memory retention were observed in the treated group. We demonstrated transplacental effects of ruxolitinib on astrogenesis, suggesting the potential use of ruxolitinib to revert pathological conditions caused by gliogenic-shift in early brain development such as Down and Noonan syndromes.

| S-EPMC7884429 | biostudies-literature

Single-cell transcriptomic analysis of the adult mouse spinal cord reveals molecular diversity of autonomic and skeletal motor neurons.

Project description:The spinal cord is a fascinating structure that is responsible for coordinating movement in vertebrates. Spinal motor neurons control muscle activity by transmitting signals from the spinal cord to diverse peripheral targets. In this study, we profiled 43,890 single-nucleus transcriptomes from the adult mouse spinal cord using fluorescence-activated nuclei sorting to enrich for motor neuron nuclei. We identified 16 sympathetic motor neuron clusters, which are distinguishable by spatial localization and expression of neuromodulatory signaling genes. We found surprising skeletal motor neuron heterogeneity in the adult spinal cord, including transcriptional differences that correlate with electrophysiologically and spatially distinct motor pools. We also provide evidence for a novel transcriptional subpopulation of skeletal motor neuron (γ*). Collectively, these data provide a single-cell transcriptional atlas ( http://spinalcordatlas.org ) for investigating the organizing molecular logic of adult motor neuron diversity, as well as the cellular and molecular basis of motor neuron function in health and disease.

| S-EPMC8016743 | biostudies-literature

Modeling Alexander disease with patient iPSCs reveals cellular and molecular pathology of astrocytes.

Project description:Alexander disease is a fatal neurological illness characterized by white-matter degeneration and formation of Rosenthal fibers, which contain glial fibrillary acidic protein as astrocytic inclusion. Alexander disease is mainly caused by a gene mutation encoding glial fibrillary acidic protein, although the underlying pathomechanism remains unclear. We established induced pluripotent stem cells from Alexander disease patients, and differentiated induced pluripotent stem cells into astrocytes. Alexander disease patient astrocytes exhibited Rosenthal fiber-like structures, a key Alexander disease pathology, and increased inflammatory cytokine release compared to healthy control. These results suggested that Alexander disease astrocytes contribute to leukodystrophy and a variety of symptoms as an inflammatory source in the Alexander disease patient brain. Astrocytes, differentiated from induced pluripotent stem cells of Alexander disease, could be a cellular model for future translational medicine.

| S-EPMC4940830 | biostudies-literature

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