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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 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.

SUBMITTER: Dr. Stefanie Ohlig

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

REPOSITORIES: biostudies-other

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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 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.

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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.

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