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Spatial centrosome proteome of human neural cells uncovers novel interactors and disease hubs

ABSTRACT: Despite the crucial importance of the centrosome in brain development and disease, its comprehensive proteome remains uncharacterized in neural cells. Here, we used spatial proteomics to elucidate protein interaction networks at the centrosome of iPSC-derived human neural stem cells (NSCs) and neurons. Centrosome-associated proteins were largely cell-type specific, with protein hubs involved in RNA-dynamics. Analysis of neurodevelopmental disease cohorts identified a significant overrepresentation of NSC centrosome proteins with variants in patients with periventricular heterotopia (PH). Expressing the PH-associated mutant splicing factor PRPF6 reproduced the periventricular misplacement in the developing mouse brain, highlighting mis-splicing of transcripts of the MAP-kinase SAD-A at centrosomal location as essential for the phenotype. Collectively, cell-type specific centrosome interactomes explain how genetic variants in ubiquitous proteins may convey brain-specific phenotypes.

ORGANISM(S): Mus musculus

PROVIDER: GSE201954 | GEO | 2022/06/15

REPOSITORIES: GEO

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Spatial centrosome proteome of human neural cells uncovers novel interactors and disease hubs

Project description:Despite the crucial importance of the centrosome in brain development and disease, its comprehensive proteome remains uncharacterized in neural cells. Here, we used spatial proteomics to elucidate protein interaction networks at the centrosome of iPSC-derived human neural stem cells (NSCs) and neurons. Centrosome-associated proteins were largely cell type-specific, with protein hubs involved in RNA dynamics. Analysis of neurodevelopmental disease cohorts identified a significant overrepresentation of NSC centrosome proteins with variants in patients with periventricular heterotopia (PH). Expressing the PH-associated mutant splicing factor PRPF6 reproduced the periventricular misplacement in the developing mouse brain, highlighting mis-splicing of transcripts of the MAP-kinase SAD-A at centrosomal location as essential for the phenotype. Collectively, cell type-specific centrosome interactomes explain how genetic variants in ubiquitous proteins may convey brain-specific phenotypes.

2022-06-22 | PXD031936 | Pride

Spatial Transcriptomics reveals brain regional gene expression profiles in murine model of Periventricular Heterotopia

Project description:Periventricular Heterotopia (PH) is a malformation of cerebral cortical development characterized by the presence of neurons along the wall of lateral ventricles. The most notable neurological symptoms are seizures that usually first appear when PH becomes evident during the teenage years. Heterozygous loss of function mutations within the FLNA gene in Xq28 are the most frequent cause of familial PH, while the genotype-phenotype correlation has not been well established. We generated a mouse model of PH by conditionally deleting Flna in neural progenitors along with a Flnb null mutation. In this mouse model, periventricular neurons are predominantly generated in postnatal ages. To understand the pathogenesis of PH and the mechanism of postnatal- adult neurogenesis, we assessed transcriptomic alterations resulting from Flna and Flnb double loss of function in the ventricular/subventricular zone (V-SVZ), upper cortical layers, and periventricular neurons, respectively. This dataset reveals spatially-dependent differential gene expressions between PH and their normal control counterparts at 3 months of age.

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Altered migratory trajectories in cerebral organoids derived from individuals with neuronal heterotopia

Project description:Malformations of the human cortex represent a major cause of disability. Mouse models with mutations in known causal genes only partially recapitulate the phenotypes and are therefore not unlimitedly suited for understanding the molecular and cellular mechanisms responsible for these conditions. Here we study periventricular heterotopia (PH) by analyzing cerebral organoids derived from induced pluripotent stem cells of patients with mutations in the cadherin receptor-ligand pair DCHS1 and FAT4 or from isogenic knock-out lines. Our results show that human cerebral organoids reproduce the cortical heterotopia associated with PH. Mutations in DCHS1 and FAT4 or knock-down of their expression cause changes in the morphology of neural progenitor cells and result in defective neuronal migration dynamics only in a subset of neurons. Single-cell RNA-sequencing data reveal a subpopulation of mutant neurons with dysregulated genes involved in axon guidance, neuronal migration and patterning. We suggest that defective neural progenitor cell (NPC) morphology and an altered navigation system in a subset of neurons underlie this form of periventricular heterotopia.

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Molecular Signature of Centrosome Abnormalities in Multiple Myeloma

Project description:A large number of cancer-associated proteins involved in the cell cycle, DNA repair, chaperoning and nucleocytoplasmic transport etc. are involved in the control of centrosome number, duplication, centrosome formation and have been implicated as origin of centrosome abnormalities in cancer. In this study, we performed gene expression profiling with focusing on centrosome-related genes for determining the molecular signature characteristic for centrosome abnormalities in MM patients.

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Project description:Centrosome amplification induces proliferation arrest and cell invasion. The fate of centrosome amplification cells are studied here.

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Oncogene-like induction of cellular invasion from centrosome amplification

Project description:Centrosome amplification has long been recognized as a feature of human tumors, however its role in tumorigenesis remains unclear. Centrosome amplification is poorly tolerated by non-transformed cells, and, in the absence of selection, extra centrosomes are spontaneously lost. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumors, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumor progression. Using a three-dimensional model system and other approaches to culture human mammary epithelial cells, we find that centrosome amplification triggers cell invasion. This invasive behavior is similar to that induced by overexpression of the breast cancer oncogene ErbB2 and indeed enhances invasiveness triggered by ErbB2. We show that, through increased centrosomal microtubule nucleation, centrosome amplification increases Rac1 activity, which disrupts normal cell-cell adhesion and promotes invasion. These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation.

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Oncogene-like induction of cellular invasion from centrosome amplification

2014-03-01 | E-GEOD-55042 | biostudies-arrayexpress

Centrosome amplification triggers tumorigenesis in p53 deficient epidermis

Project description:While aneuploidy is found in more than 90% of solid tumors, it is unclear whether aneuploidy is the cause or the consequence of tumorigenesis. Different mouse models deficient in centrosomal or spindle checkpoint proteins that induce aneuploidy show either a promotion or a decrease in tumorigenesis depending on the tissues and the types of oncogenic stimuli. To investigate the effects of aneuploidy in skin development and tumorigenesis, we used Plk4 over-expression (Plk4OE) during epidermal development to assess centrosome amplification and aneuploidy. We found that PLK4OE in the developing epidermis induced centrosome amplification and multipolar divisions, consequently led to p53 stabilization and apoptosis of epidermal progenitors. This delayed epidermal stratification and induced lethal skin barrier defect in 50% of the mice. Plk4 transgene expression was shutdown postnatally in the surviving mice and PLK4OE mice never developed spontaneous skin tumors. Concomitant Plk4OE and P53 deletion (PLK4OE/p53cKO) rescued the defects in differentiation and stratification. Unexpectedly, p53 deletion did not rescue the apoptosis or eventual elimination of the cells overexpressing PLK4 and presenting multiple centrosomes. Remarkably, the short term presence of cells with supernumerary centrosomes postnatally was sufficient to generate aneuploidy and triggered spontaneous skin cancers with complete penetrance. These results reveal for the first time that aneuploidy induced by centrosome amplification, even if transient, can trigger tumorigenesis.

2015-10-27 | E-MTAB-3733 | biostudies-arrayexpress

CEP120 Promotes Centrosome Amplification And Progression Of Gastric Cancer Via USP54-Mediated Deubiquitination Of PLK4

Project description:Centrosomal protein 120 (CEP120) is a 120kD centrosome protein that plays an important role in centrosome replication. Overexpression of CEP120 can lead to centrosome amplification, which is closely associated with tumorigenesis and development. However, there are no reports on the relationship between CEP120 and tumors. In our study, overexpression of CEP120 promoted centrosome amplification in gastric cancer (GC), and the role of CEP120 in promoting GC progression was demonstrated in vitro and in vivo. We demonstrated that CEP120 promotes centrosome amplification and GC progression by promoting the expression and centrosome aggregation of the deubiquitinating enzyme USP54, maintaining the stability of PLK4 and reducing its ubiquitination degradation. In conclusion, the CEP120-USP54-PLK4 axis may play an important role in promoting centrosome amplification and GC progression, thus providing a potential therapeutic target for GC.

2023-01-04 | GSE217567 | GEO

Dynamic role of Rotatin in mitosis, ciliogenesis and nucleokinesis correlates with variable mutant cerebral phenotypes.

Project description:Recessive mutations in RTTN, encoding centrosome associated protein Rotatin, were originally identified as cause of polymicrogyria, a cortical malformation. With time a wide variety of other brain malformations has been ascribed to RTTN mutations, such as primary microcephaly. However, the function of Rotatin is largely unknown and the molecular disease mechanism underlying these malformations has not yet been elucidated. Here, we report four novel families identified by high throughput sequencing, one of them with a novel deep intronic variant. We reviewed RTTN-related disease phenotypes and defined the spectrum which includes intellectual disability (ID), short stature, microcephaly, lissencephaly, periventricular heterotopia, polymicrogyria and other malformations. Rotatin expression, function and cellular disease phenotype were studied in cultured primary skin fibroblasts from eight unrelated affected individuals. We found that Rotatin deficiency leads to abnormal centrosome amplification during mitosis, resulting in multipolar spindle formation, mitotic failure, increased apoptosis and aneuploidy. In non-dividing healthy cells, Rotatin localizes at the primary cilium, both at basal body and axoneme during ciliogenesis. Interestingly, interphase mutant cells show aberrant ciliogenesis. Proteomics analysis reveals that exogenous Rotatin in HEK293 cells interacts with the non-muscle cellular myosin complex (MYH9-MYH10-MYH14), which is essential for nucleokinesis during neuronal migration. In hiPSC-derived neurons, endogenous Rotatin localizes to the leading edge centrosome, which pulls the perinuclear cage during nucleokinesis, suggesting a pivotal role of Rotatin in neuronal migration. This study sheds light on the pleiotropic cellular functions of Rotatin, explaining disease spectrum linked to both neuronal proliferation and migration.

2019-03-25 | PXD012415 | Pride

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