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The bone transcription factor Osterix controls extracellular matrix and node of Ranvier related gene expression in oligodendrocytes

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE221193 | GEO | 2023/09/08

REPOSITORIES: GEO

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The bone transcription factor Osterix controls extracellular matrix and node of Ranvier related gene expression in oligodendrocytes [RNA-seq]

Project description:Oligodendrocytes are the primary producers of many extracellular matrix (ECM) related proteins found in the central nervous system (CNS), thereby, these cells play a critical role in the determination of brain stiffness, node of Ranvier formation, perinodal ECM deposition and perineuronal net formation. The transcription factors that control ECM related gene expression in oligodendrocytes remain unknown. Here, we found that the transcription factor Osterix (also known as Sp7) binds in proximity to genes important for CNS ECM and node of Ranvier formation and mediates their expression. Oligodendrocyte specific ablation of Sp7 changes ECM composition and brain stiffness, and results in aberrant node of Ranvier formation. Sp7 is known to control osteoblast maturation and bone formation. Our comparative analyses suggests that Sp7 plays a conserved biological role in oligodendrocytes and in bone forming cells, where it mediates brain and bone tissue stiffness by controlling the expression of ECM components.

2023-09-11 | GSE221192 | GEO

The bone transcription factor Osterix controls extracellular matrix and node of Ranvier related gene expression in oligodendrocytes [ChIP-seq]

2023-09-11 | GSE221191 | GEO

The bone transcription factor Osterix controls extracellular matrix and node of Ranvier related gene expression in oligodendrocytes [ATAC-seq]

2023-09-11 | GSE221189 | GEO

The bone transcription factor Osterix controls extracellular matrix and node of Ranvier related gene expression in oligodendrocytes

Project description:The bone transcription factor Osterix controls extracellular matrix and node of Ranvier related gene expression in oligodendrocytes

| PRJNA913170 | ENA

The bone transcription factor Osterix controls extracellular matrix and node of Ranvier related gene expression in oligodendrocytes [ChIP-seq]

Project description:The bone transcription factor Osterix controls extracellular matrix and node of Ranvier related gene expression in oligodendrocytes [ChIP-seq]

| PRJNA913272 | ENA

The bone transcription factor Osterix controls extracellular matrix and node of Ranvier related gene expression in oligodendrocytes [ATAC-seq]

Project description:The bone transcription factor Osterix controls extracellular matrix and node of Ranvier related gene expression in oligodendrocytes [ATAC-seq]

| PRJNA913273 | ENA

The bone transcription factor Osterix controls extracellular matrix and node of Ranvier related gene expression in oligodendrocytes [RNA-seq]

Project description:The bone transcription factor Osterix controls extracellular matrix and node of Ranvier related gene expression in oligodendrocytes [RNA-seq]

| PRJNA913271 | ENA

Sclerostin is a direct target of osteoblast-specific transcription factor osterix.

Project description:Osterix (Osx) is an osteoblast-specific transcription factor required for osteoblast differentiation and bone formation. Osx knock-out mice lack bone completely. Recent findings that Osx inhibits Wnt signaling provide a feedback control mechanism involved in bone formation. Mechanisms of Osx inhibition on Wnt signaling are not fully understood. Our results in this study revealed that the expression of a Wnt antagonist Sclerostin (Sost) was downregulated in Osx-null calvaria. Overexpression of Osx in stable C2C12 mesenchymal cell line resulted in Sost upregulation. Transient transfection assay showed that Osx activated 1kb Sost promoter reporter activity in a dose-dependent manner. To define Sost promoter activated by Osx, we made a series of deletion mutants of Sost constructs, and narrowed down the minimal region to the proximal 260bp. Gel shift assay indicated that Osx bound to GC-rich site within this minimal region, and that point mutations of this binding site disrupted Osx binding. Moreover, the same point mutations in 260bp Sost promoter reporter disrupted the promoter activation by Osx, suggesting that the GC-rich binding site was responsible for Sost promoter activation by Osx. To further examine physical association of Osx with Sost promoter in vivo, Chromatin immunoprecipitation (ChIP) assays were performed using primary osteoblasts from mouse calvaria. Osx was found to associate with endogenous Sost promoter. Taken together, these findings support our hypothesis that Sost is a direct target of Osx. This provides a new additional mechanism through which Osx inhibits Wnt signaling during bone formation.

| S-EPMC4041335 | biostudies-literature

The transcription factor osterix (SP7) regulates BMP6-induced human osteoblast differentiation.

Project description:The transcription factor osterix (Sp7) is essential for osteoblastogenesis and bone formation in mice. Genome wide association studies have demonstrated that osterix is associated with bone mineral density in humans; however, the molecular significance of osterix in human osteoblast differentiation is poorly described. In this study we have characterized the role of osterix in human mesenchymal progenitor cell (hMSC) differentiation. We first analyzed temporal microarray data of primary hMSC treated with bone morphogenetic protein-6 (BMP6) using clustering to identify genes that are associated with osterix expression. Osterix clusters with a set of osteoblast-associated extracellular matrix (ECM) genes, including bone sialoprotein (BSP) and a novel set of proteoglycans, osteomodulin (OMD), osteoglycin, and asporin. Maximum expression of these genes is dependent upon both the concentration and duration of BMP6 exposure. Next we overexpressed and repressed osterix in primary hMSC using retrovirus. The enforced expression of osterix had relatively minor effects on osteoblastic gene expression independent of exogenous BMP6. However, in the presence of BMP6, osterix overexpression enhanced expression of the aforementioned ECM genes. Additionally, osterix overexpression enhanced BMP6 induced osteoblast mineralization, while inhibiting hMSC proliferation. Conversely, osterix knockdown maintained hMSC in an immature state by decreasing expression of these ECM genes and decreasing mineralization and hMSC proliferation. Overexpression of the osterix regulated gene OMD with retrovirus promoted mineralization of hMSC. These results suggest that osterix is necessary, but not sufficient for hMSC osteoblast differentiation. Osterix regulates the expression of a set of ECM proteins which are involved in terminal osteoblast differentiation.

| S-EPMC3241898 | biostudies-literature

Inhibition of Wnt signaling by the osteoblast-specific transcription factor Osterix.

Project description:The recent identification of the genes responsible for several human genetic diseases affecting bone homeostasis and the characterization of mouse models for these diseases indicated that canonical Wnt signaling plays a critical role in the control of bone mass. Here, we report that the osteoblast-specific transcription factor Osterix (Osx), which is required for osteoblast differentiation, inhibits Wnt pathway activity. First, in calvarial cells of embryonic day (E)18.5 Osx-null embryos, expression of the Wnt antagonist Dkk1 was abolished, and that of Wnt target genes c-Myc and cyclin D1 was increased. Moreover, our studies demonstrated that Osx bound to and activated the Dkk1 promoter. In addition, Osx inhibited beta-catenin-induced Topflash reporter activity and beta-catenin-induced secondary axis formation in Xenopus embryos. Importantly, in calvaria of E18.5 Osx-null embryos harboring the TOPGAL reporter transgene, beta-galactosidase activity was increased, suggesting that Osx inhibited the Wnt pathway in osteoblasts in vivo. Our data further showed that Osx disrupted binding of Tcf to DNA, providing a likely mechanism for the inhibition by Osx of beta-catenin transcriptional activity. We also showed that Osx decreased osteoblast proliferation. Indeed, E18.5 Osx-null calvaria showed greater BrdU incorporation than wild-type calvaria and that Osx overexpression in C2C12 mesenchymal cells inhibited cell growth. Because Wnt signaling has a major role in stimulating osteoblast proliferation, we speculate that Osx-mediated inhibition of osteoblast proliferation is a consequence of the Osx-mediated control of Wnt/beta-catenin activity. Our results add a layer of control to Wnt/beta-catenin signaling in bone.

| S-EPMC2383965 | biostudies-literature