Plexin-B2 reduces glioma cell cohesion and regulates glioma-vascular interactions
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ABSTRACT:
PROVIDER: PRJNA522815 | ENA |
REPOSITORIES: ENA
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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.
2021-09-07 | GSE158017 | 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: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:Plexin-B2 regulates mechanotension during multicellular organization
| PRJNA663651 | 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.
2016-06-29 | PXD001249 | Pride
Project description:After central nervous system injury, a rapid neuroinflammatory response is induced. This response can be both beneficial and detrimental to neuronal survival in the first few days and increase the risk for neurodegeneration if it persists. Semaphorin4B (Sema4B), a transmembrane protein primarily expressed by cortical astrocytes, has been shown to play a role in neuronal cell death following injury. Our study shows that neuroinflammation is attenuated in Sema4B knockout mice and microglia/macrophage activation is reduced after cortical stab wound injury. In vitro, recombinant Sema4B enhances the activation of microglia following injury, suggesting astrocytic Sema4B functions as a ligand. Moreover, injury-induced activation of microglia is attenuated in the presence of Sema4B knockout astrocytes compared to heterozygous astrocytes. In vitro, experiments indicate Plexin-B2 is the Sema4B receptor on microglia. Consistent with this, microglia-specific Plexin-B2 knockout mice, similar to Sema4B knockout mice, also show a reduction in microglial activation after cortical injury. Finally, in Sema4B/Plexin-B2 double heterozygous mice, microglial activation is also reduced after injury, thus supporting the idea that both Sema4B and Plexin-B2 are part of the same signaling pathway. Taken together, we propose a model in which following injury, astrocytic Sema4B enhances the pro-inflammatory response of microglia/macrophages via Plexin-B2, leading to increased neuroinflammation.
2024-02-28 | GSE230069 | GEO
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
Project description:Correct chromosome segregation requires that sister chromatids are held together by the protein complex cohesin, from S phase until anaphase. This S phase established cohesion is, together with DSB recruitment of cohesin and formation of damage induced (DI) cohesion, also important for repair of DSBs. Eco1 is a common essential factor for S phase and DI-cohesion. The fission yeast Eco1ortholog, Eso1, is important both for S phase cohesion and for bypass of UV induced lesions, and is expressed as a fusion protein with Polη. The cohesion function has been attributed solely to Eso1 and the lesion bypass function to the Polη part of the protein. As we found the interaction between the two proteins intriguing we decided to look for a functional connection also in budding yeast. Indeed, despite being dispensable for S phase cohesion, budding yeast Polη is required for formation of DI genome-wide cohesion. However, Polη deficient cells are DSB repair competent, revealing differential regulation of DI-cohesion at the break and genome-wide. This finding challenges the importance of DI genome-wide cohesion for DSB repair, and based on our findings we suggest that S phase cohesion is not sufficient for correct chromosome segregation in the presence of DNA damage.
2013-01-15 | GSE42655 | GEO
Project description:Sulfurimonas sp. B2 strain:B2 Genome sequencing
| PRJNA549374 | ENA