Plexin-B2 reduces glioma cell cohesion and regulates glioma-vascular interactions
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA522815 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8583380_1.fastq.gz | Fastqsanger.gz | |||
| SRR8583380_2.fastq.gz | Fastqsanger.gz | |||
| SRR8583390_1.fastq.gz | Fastqsanger.gz | |||
| SRR8583390_2.fastq.gz | Fastqsanger.gz | |||
| SRR8583400_1.fastq.gz | Fastqsanger.gz |
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Project description:The diffuse invasion of glioblastoma (GBM) cells into healthy brain tissue is a main contributor for the high lethality of this most frequent form of malignant brain tumor. Plexins are cell surface receptors for semaphorins and control cell adhesion and cytoskeletal dynamics in development and in adult physiology. Gene expression of Plexin-B2 is upregulated in GBM and correlates with its lethality. We show here that Plexin-B2 activity can reduce the cohesiveness of GBM cells, which facilitates their invasive capacity. Targeted deletion of Plexin-B2 in GBM cells increased their cohesion to each other, revealing that a major function of Plexin-B2 activity is to downregulate cell-cell adhesion, possibly by downregulating other cell adhesion systems. In an in vivo intracranial transplant model, invasion of Plexin-B2 mutant GBM cells was impaired, with cells invading shorter distances. Interestingly, the loss of Plexin-B2 also changed the migration mode of cells, with the balance of cells in brain stroma vs. capillary space shifted: Plexin-B2 mutant cells were more likely to adhere to the vasculature. Our structure-function analyses revealed that the Ras-GAP domain of Plexin-B2 that is the main functional output responsible for the cohesion regulating function of Plexin-B2. Transcriptomic analyses of Plexin-B2 KO cells suggests that Plexin-B2 loss in different GBM cell lines has no direct transcriptional target genes, however, consistently, cell adhesion molecules were changed in expression, suggesting that cells compensate for loss of Plexin-B2. Thus, Plexin-B2 acts as a key regulator of the cohesiveness of GBM cells, thereby facilitating their invasiveness.
2021-01-13 | GSE126658 | GEO
Project description:During multicellular organization, individual cells need to constantly adjust intracellular contractility and junctional adhesive properties in order to maintain tissue cohesion and mechanotension. The membrane receptors linking external biochemical cues and internal cell mechanics are incompletely understood. Here, we reveal that the axon guidance receptor Plexin-B2 regulates intracellular mechanotension, and this in turn impacts cell-cell/cell-matrix adhesiveness during self-assembly of human embryonic stem cells (hESCs) and neuroprogenitor cells (hNPCs) into epithelial structures. The altered tissue mechanics caused by Plexin-B2 deficiency or over expression affects stem cell behaviors as well as β-catenin and YAP mechanosensing. Strikingly, Plexin-B2 deficiency results in accelerated neuronal differentiation, while proper levels of Plexin-B2 activity are required for maintaining cytoarchitectural integrity of the neuroepithelium as modeled in cerebral organoids. Mechanistically, Plexin-B2 engages its extracellular and Ras-GAP domains for mechanoregulation via RAP1/2. Our studies establish mechanoregulation as a key function of Plexin-B2 during multicellular organization, thereby solidifying the principle of force- mediated regulation of stem cell biology and tissue morphogenesis.
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Project description:Tissue repair after spinal cord injury (SCI) requires mobilization of immune and glial cells to form a protective barrier that seals the wound and facilitates debris clearing, inflammatory containment, and matrix compaction. This process involves corralling, wherein phagocytic immune cells become confined to the necrotic core surrounded by an astrocytic border. Here, we elucidate a temporally distinct gene signature in injury-activated microglia/macrophages (IAM), which engages axon guidance pathways. Plexin-B2 is upregulated in IAM, which is required for motosensory recovery after SCI. Plexin-B2 deletion in myeloid cells impairs corralling, leading to diffuse tissue damage, inflammatory spillover, and hampered axon regeneration. Corralling begins early and requires Plexin-B2 in both microglia and macrophages. Mechanistically, Plexin-B2 promotes microglia motility, steers IAM away from colliding cells, and facilitates matrix compaction. Our data thus establish Plexin-B2 as an important link that integrates biochemical cues and physical interactions of IAM with the injury microenvironment during wound healing.
2019-12-23 | GSE113566 | GEO
Project description:To identify Plexin-B2-associated proteins, articular chondrocytes were untreated or treated with Sema4D. Plexin-B2-bound proteins were purified by immunoprecipitation using an anti-Plexin-B2 antibody, followed by mass spectrometry.
2022-11-01 | PXD034551 | JPOST Repository
Project description:Plexin-B2 regulates mechanotension during multicellular organization
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Project description:Follicular T-helper (TFH) cells are essential for germinal center (GC) responses. TFH localization in GCs is controlled by chemo-guidance cues and antigen-specific adhesion. Here we define an antigen-independent, contact-dependent, adhesive guidance system for TFH cells. Unusual for amoeboid cell migration, the system is composed of transmembrane plexin B2 (PlxnB2) molecule that is highly expressed by GC B cells and its transmembrane binding partner semaphorin 4C (Sema4C) that is upregulated on TFH cells. Instead of effectuating repulsion as a ligand, Sema4C serves as the receptor to sense PlxnB2 and bias TFH migration inward at the GC edge to penetrate the GC territory. The absence of PlxnB2 from the GC or Sema4C from TFH cells causes TFH accumulation along the GC border, impairs TFH -B cell interactions and is associated with defective plasma cell production and affinity maturation. Therefore, Sema4C and PlxnB2 regulate GC TFH recruitment and function and optimal antibody responses.
2017-06-12 | GSE96819 | GEO
Project description:Invasive growth is a major determinant of the high lethality of malignant gliomas. Plexin-B2, an axon guidance receptor important for mediating neural progenitor cell migration during development, is upregulated in gliomas, but its function therein remains poorly understood. Combining bioinformatic analyses, immunoblotting and immunohistochemistry of patient samples, we demonstrate that Plexin-B2 is consistently upregulated in all types of human gliomas and that its expression levels correlate with glioma grade and poor survival. Activation of Plexin-B2 by Sema4C ligand in glioblastoma cells induced actin-based cytoskeletal dynamics and invasive migration in vitro. This proinvasive effect was associated with activation of the cell motility mediators RhoA and Rac1. Furthermore, costimulation of Plexin-B2 and the receptor tyrosine kinase Met led to synergistic Met phosphorylation. In intracranial glioblastoma transplants, Plexin-B2 knockdown hindered invasive growth and perivascular spreading, and resulted in decreased tumor vascularity. Our results demonstrate that Plexin-B2 promotes glioma invasion and vascularization, and they identify Plexin-B2 as a potential novel prognostic marker for glioma malignancy. Targeting the Plexin-B2 pathway may represent a novel therapeutic approach to curtail invasive growth of glioblastoma.
| S-EPMC4466685 | biostudies-literature
Project description:Although splicing is essential for the expression of most eukaryotic genes, inactivation of splicing factors causes specific defects in mitosis. The molecular cause of this defect is unknown. Here we show that the spliceosome subunits SNW1 and PRPF8 are essential for sister chromatid cohesion in human cells. A transcriptome-wide analysis revealed that SNW1 or PRPF8 depletion affects the splicing of specific introns in a subset of pre-mRNAs, including pre-mRNAs encoding the cohesion protein sororin and the APC/C subunit APC2. SNW1 depletion causes cohesion defects predominantly by reducing sororin levels, which causes destabilisation of cohesin on DNA. SNW1 depletion also reduces APC/C activity and contributes to cohesion defects indirectly by delaying mitosis and causing ‘cohesion fatigue’. Simultaneous expression of sororin and APC2 from intron-less cDNAs restores cohesion in SNW1 depleted cells. These results indicate that the spliceosome is required for mitosis because it enables expression of genes essential for cohesion. Our transcriptome-wide identification of retained introns in SNW1 and PRPF8 depleted cells may help to understand the aetiology of diseases associated with splicing defects, such as retinosa pigmentosum and cancer.
2016-06-29 | PXD001249 | Pride
Project description:Microglia and macrophages promote corralling, wound compaction and recovery in spinal cord injury via Plexin-B2
| PRJNA451532 | ENA
Project description:Although splicing is essential for the expression of most eukaryotic genes, inactivation of splicing factors causes specific defects in mitosis. The molecular cause of this defect is unknown. Here we show that the spliceosome subunits SNW1 and PRPF8 are essential for sister chromatid cohesion in human cells. A transcriptome-wide analysis revealed that SNW1 or PRPF8 depletion affects the splicing of specific introns in a subset of pre-mRNAs, including pre-mRNAs encoding the cohesion protein sororin and the APC/C subunit APC2. SNW1 depletion causes cohesion defects predominantly by reducing sororin levels, which causes destabilisation of cohesin on DNA. SNW1 depletion also reduces APC/C activity and contributes to cohesion defects indirectly by delaying mitosis and causing ‘cohesion fatigue’. Simultaneous expression of sororin and APC2 from intron-less cDNAs restores cohesion in SNW1 depleted cells. These results indicate that the spliceosome is required for mitosis because it enables expression of genes essential for cohesion. Our transcriptome-wide identification of retained introns in SNW1 and PRPF8 depleted cells may help to understand the aetiology of diseases associated with splicing defects, such as retinosa pigmentosum and cancer.
2017-04-02 | MSV000080878 | MassIVE