Extracellular matrix-inducing Sox9 orchestrates basal progenitor proliferation and gliogenesis in developing neocortex
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA554116 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9672140.fastq.gz | Fastqsanger.gz | |||
| SRR9672141.fastq.gz | Fastqsanger.gz | |||
| SRR9672142.fastq.gz | Fastqsanger.gz | |||
| SRR9672143.fastq.gz | Fastqsanger.gz | |||
| SRR9672144.fastq.gz | Fastqsanger.gz |
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Project description:Neocortex expansion is largely based on the proliferative capacity of basal progenitors (BPs), which is increased by extracellular matrix (ECM) components via integrin signaling. Here we show that Sox9 drives expression of ECM components and that laminin 211 increases BP proliferation in embryonic mouse neocortex. Examination of Sox9 expression reveals that Sox9 is expressed in BPs of developing ferret and human, but not mouse neocortex. Functional studies by conditional Sox9 expression in the mouse BP lineage demonstrate increased BP proliferation, reduced Tbr2 and induction of Olig2 expression, indicative of premature gliogenesis. Conditional Sox9 expression also results in cell non-autonomous stimulation of BP proliferation followed by increased production of upper-layer neurons. Collectively, our findings demonstrate that Sox9 exerts concerted effects on transcription, BP proliferation, neuron production, and neurogenic as well as gliogenic BP cell fate, suggesting that Sox9 acts a master regulator in the subventricular zone to promote neocortical expansion.
2020-03-27 | GSE134162 | GEO
Project description:Neocortex expansion is largely based on the proliferative capacity of basal progenitors (BPs), which is increased by extracellular matrix (ECM) components via integrin signaling. Here we show that the transcription factor Sox9 drives expression of ECM components and that laminin 211 increases BP proliferation in embryonic mouse neocortex. We show that Sox9 is expressed in human and ferret BPs and is required for BP proliferation in embryonic ferret neocortex. Conditional Sox9 expression in the mouse BP lineage, where it normally is not expressed, increases BP proliferation, reduces Tbr2 levels and induces Olig2 expression, indicative of premature gliogenesis. Conditional Sox9 expression also results in cell-non-autonomous stimulation of BP proliferation followed by increased upper-layer neuron production. Our findings demonstrate that Sox9 exerts concerted effects on transcription, BP proliferation, neuron production, and neurogenic vs. gliogenic BP cell fate, suggesting that Sox9 may have contributed to promote neocortical expansion.
| S-EPMC7105383 | biostudies-literature
Project description:Vascular endothelial cells drive organ fibrosis by inducing the transcription factor Sox9
| PRJNA813510 | ENA
Project description:Fibrosis is a hallmark of chronic disease. Although fibroblasts are known to be involved, it is unclear to what extent endothelial cells might contribute. We detected increased expression of the transcription factor Sox9 in endothelial cells of fibrotic mouse organs in models of systolic heart failure by pressure overload, diastolic heart failure by high-fat diet and L-Name administration, pulmonary fibrosis after bleomycin treatment, and liver fibrosis as consequence of CDAA diet. We also observed endothelial SOX9 upregulation in human heart tissue in patients with heart failure. To test whether this SOX9 induction was sufficient to cause disease, we generated mice with endothelial cell-specific overexpression of Sox9, which indeed triggered extensive fibrosis in multiple organs and promoted signs of heart failure. Endothelial Sox9 deletion, in turn, prevented fibrosis and organ dysfunction in pre-clinical surgical and pharmacological mouse models of heart failure as well as of lung, and liver injury. Bulk and single cell RNA sequencing of endothelial cells across multiple vascular beds revealed that SOX9 induced extracellular matrix, growth factor, and inflammatory genes leading to matrix deposition by endothelial cells. Moreover, in part through triggering an increased expression of the secreted growth factor Ccn2 as direct SOX9 target, endothelial cells activated neighboring fibroblasts to migrate and deposit matrix in response to SOX9. Endothelial Sox9 deletion reversed these changes, suggesting a role for endothelial SOX9 as fibrosis-promoting transcription factor across organs in response to disease stimuli. Therefore, endothelial cells could be a promising target to counteract fibrotic heart, liver and lung disease
2023-12-29 | GSE252082 | GEO
Project description:Fibrosis is a hallmark of chronic disease. Although fibroblasts are known to be involved, it is unclear to what extent endothelial cells might contribute. We detected increased expression of the transcription factor Sox9 in endothelial cells of fibrotic mouse organs in models of systolic heart failure by pressure overload, diastolic heart failure by high-fat diet and L-Name administration, pulmonary fibrosis after bleomycin treatment, and liver fibrosis as consequence of CDAA diet. We also observed endothelial SOX9 upregulation in human heart tissue in patients with heart failure. To test whether this SOX9 induction was sufficient to cause disease, we generated mice with endothelial cell-specific overexpression of Sox9, which indeed triggered extensive fibrosis in multiple organs and promoted signs of heart failure. Endothelial Sox9 deletion, in turn, prevented fibrosis and organ dysfunction in pre-clinical surgical and pharmacological mouse models of heart failure as well as of lung, and liver injury. Bulk and single cell RNA sequencing of endothelial cells across multiple vascular beds revealed that SOX9 induced extracellular matrix, growth factor, and inflammatory genes leading to matrix deposition by endothelial cells. Moreover, in part through triggering an increased expression of the secreted growth factor Ccn2 as direct SOX9 target, endothelial cells activated neighboring fibroblasts to migrate and deposit matrix in response to SOX9. Endothelial Sox9 deletion reversed these changes, suggesting a role for endothelial SOX9 as fibrosis-promoting transcription factor across organs in response to disease stimuli. Therefore, endothelial cells could be a promising target to counteract fibrotic heart, liver and lung disease
2023-12-29 | GSE252081 | GEO
Project description:Vascular calcification and increased extracellular matrix (ECM) stiffness are hallmarks of vascular ageing. Sox9 (SRY-Box Transcription Factor 9) is a master regulator of chondrogenesis, also expressed in the vasculature, that has been implicated in vascular smooth muscle cell (VSMC) osteo-chondrogenic conversion. Here, we investigated the relationship between vascular ageing, calcification and Sox9-driven ECM regulation in VSMCs. Immunohistochemistry in human aortic samples showed that Sox9 was not spatially associated with vascular calcification but correlated with the senescence marker p16. Analysis of Sox9 expression in vitro showed it was mechanosensitive with increased expression and nuclear translocation in senescent cells and on stiff matrices. Manipulation of Sox9 via overexpression and depletion, combined with atomic force microscopy (AFM) and proteomics, revealed that Sox9 regulates ECM stiffness and organisation by orchestrating changes in collagen expression and reducing VSMC contractility, leading to the formation of an ECM that mirrored that of senescent cells. These ECM changes promoted phenotypic modulation of VSMCs whereby senescent cells plated onto ECM synthesized from cells depleted of Sox9 returned to a proliferative state, while proliferating cells on a matrix produced by Sox9 expressing cells showed reduced proliferation and increased DNA damage, reiterating features of senescent cells. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (LH3) was identified as a Sox9 target, and key regulator of ECM stiffness. LH3 is packaged into extracellular vesicles (EVs) and Sox9 promoted EV secretion, leading to increased LH3 deposition within the ECM. These findings identify cellular senescence and Sox9 as a key regulators of ECM stiffness during VSMC ageing and highlight a crucial role for ECM structure and composition in regulating VSMC phenotype. We identify a positive feedback cycle whereby cellular senescence and increased ECM stiffening promote Sox9 expression which drives further ECM modifications that act to accelerate vascular stiffening and cellular senescence.
2024-06-16 | PXD046001 | Pride
Project description:Endothelial cells drive organ fibrosis and dysfunction by inducing the transcription factor SOX9 (CUTNTAG)
| PRJNA1057300 | ENA
Project description:Chronic fibrosis is a hallmark of pathologic tissue remodelling that deteriorates organ function and eventually leads to death. Although fibroblasts are typically made responsible, it was recently suggested that endothelial cells contribute to fibrosis, although the functional importance of this phenomenon remained unclear. In this study, we addressed this question by genetic manipulation of the fibrogenic HMG-box transcription factor SOX9 specifically in vascular endothelial cells. Induced transgenic overexpression of SOX9 in these cells in mice triggered extensive fibrosis, organ growth and dysfunction in the heart, lung, liver and spleen. We found an upregulation of endogenous Sox9 in endothelial cells during cardiac, lung and liver fibrosis, and endothelial specific Sox9 deletion prevented fibrosis and organ dysfunction in mouse models of systolic and diastolic heart failure, as well as in mouse bleomycin induced pulmonary and non-alcoholic steato-hepatitis (NASH) triggered liver fibrosis. Mechanistically, a combined approach of bulk and single cell RNA sequencing of endothelial cells across multiple vascular beds revealed that Sox9 promoted the expression of extracellular matrix and matrix remodelling genes, growth factors, and inflammatory mediators, which triggered the expression of extracellular matrix directly by endothelial cells, but also activated fibroblasts. As we found the upregulation of endothelial Sox9 also in failing human hearts, we propose that endothelial Sox9 could be a target for anti-fibrotic therapy.
2023-12-19 | GSE198039 | GEO
Project description:Chronic fibrosis is a hallmark of pathologic tissue remodelling that deteriorates organ function and eventually leads to death. Although fibroblasts are typically made responsible, it was recently suggested that endothelial cells contribute to fibrosis, although the functional importance of this phenomenon remained unclear. In this study, we addressed this question by genetic manipulation of the fibrogenic HMG-box transcription factor SOX9 specifically in vascular endothelial cells. Induced transgenic overexpression of SOX9 in these cells in mice triggered extensive fibrosis, organ growth and dysfunction in the heart, lung, liver and spleen. We found an upregulation of endogenous Sox9 in endothelial cells during cardiac, lung and liver fibrosis, and endothelial specific Sox9 deletion prevented fibrosis and organ dysfunction in mouse models of systolic and diastolic heart failure, as well as in mouse bleomycin induced pulmonary and non-alcoholic steato-hepatitis (NASH) triggered liver fibrosis. Mechanistically, a combined approach of bulk and single cell RNA sequencing of endothelial cells across multiple vascular beds revealed that Sox9 promoted the expression of extracellular matrix and matrix remodelling genes, growth factors, and inflammatory mediators, which triggered the expression of extracellular matrix directly by endothelial cells, but also activated fibroblasts. As we found the upregulation of endothelial Sox9 also in failing human hearts, we propose that endothelial Sox9 could be a target for anti-fibrotic therapy.
2023-12-19 | GSE198040 | GEO