Autism-linked Cullin3 germline haploinsufficiency severely impacts mouse brain development and cortical neurogenesis through RhoA signaling
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ABSTRACT:
PROVIDER: PRJNA602627 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10950400_1.fastq.gz | Fastqsanger.gz | |||
| SRR10950400_2.fastq.gz | Fastqsanger.gz | |||
| SRR10950401_1.fastq.gz | Fastqsanger.gz | |||
| SRR10950401_2.fastq.gz | Fastqsanger.gz | |||
| SRR10950402_1.fastq.gz | Fastqsanger.gz |
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Project description:E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for Neurodevelopmental Disorders such as Autism Spectrum Disorder (ASD) and Developmental Delay (DD). This study identifies the impact of the ASD-associated de novo Cul3-mutation on brain anatomy, behavior, molecular, cellular, and circuit-level mechanisms during early neocortical development. We report that Cul3 mutant mice have microcephaly and severe brain structure defects. This mouse model exhibits social and cognitive deficits and hyperactivity behavior. Spatiotemporal transcriptomic and proteomic profiling of Cul3 mouse brain implicates neurogenesis and cytoskeletal defects as key drivers of Cul3 functional effect. We show that Cul3 is critical for neuron growth and development. Cultured cortical neurons from the mutant mice have reduced dendritic length, actin cytosketon defects, reduced network activity, and increased cell death. At the molecular level, we implicate upregulation of small GTPase RhoA, involved in regulation of cytoskeletal dynamics, and neurite outgrowth as one of the pathways impacted by the de novo Cul3 mutations in ASD. Treatment with small molecule RhoA inhibitor Rhosin rescues dendrite length phenotype and implicates RhoA pathway in ASD.
2021-03-16 | GSE144046 | GEO
Project description:E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for neurodevelopmental disorders including autism spectrum disorder (ASD) and developmental delay (DD). We generated Cul3-haploinsufficient mouse model to investigate brain anatomy, behavior, molecular, cellular, and circuit-level mechanisms dysregulated by Cul3 mutations. Spatiotemporal transcriptomic and proteomic profiling of the brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Quantitative proteomic profiling was performed by Tandem Mass Tag (TMT) labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis with SPS-MS3 workflow.
2020-01-22 | MSV000084830 | MassIVE
Project description:KANK1 was found as a tumor suppressor gene based on frequent deletions in renal cell carcinoma and the inhibitory activity of tumor cell proliferation. Previously, we reported that knockdown of KANK1 induced centrosomal amplification, leading to abnormal cell division, through the hyperactivation of RhoA small GTPase. Here, we explored to the effect of loss of function of KANK1 through CRISPR/Cas9-based genome editing to knockout the gene. After several rounds of genome editing, however, there were no cell lines with complete loss of KANK1, and it was found that less the wild-type KANK1 dosage was, greater the number of cells with abnormal numbers of centrosomes and the rates of cell-doubling times and apoptosis were, suggesting the involvement of KANK1 haploinsufficiency in centrosome aberrations. RNA-sequencing analysis of the cells with reduced dosages of functional KANK1 revealed potential involvement of other cell proliferation-related genes, such as EGR1, MDGA2 and BMP3, which were reported to show haploinsufficiency when they function. Thus, haploinsufficiency of KANK1 may contribute to centrosome aberrations through the network of haploinsufficiency-related genes.
2023-12-31 | GSE233700 | GEO
Project description:The present study shows by in vivo experiments, the impact of RhoA inhibitor treatment using a functionalized alginate scaffold and the beneficial results at the early stage by increasing neurites outgrowth and synaptic contact. However, 7 days after treatment a plateau is obtained in BBB score. We thus performed an in vitro and proteomic associated to systemic biology analyses of secreted factors from ND7/23 DRG cell line incubated with secreted factors from different segments after spinal cord lesion treated wih RhoA inhibitor. We then performed a time course proteomic study from the DRG cells in same conditions as for the secretome. The results taken together allow a better understanding of the mechanisms occurring in both side of the lesion and led a positive impact of the treatment on growth cone guidance in both sides of the lesion (Rostral 1 and Caudal 1). We identified the transcription factors involved in time course at the beginning of the treatment and the growth cone factors (receptors, ligands, signaling pathways) implicated in this time course. We also demonstrate the involvement of immunoglobulins (IgG1, IgG2) in this process. Anti-GFAP seem to bind to its own receptor in DRG cells when neurite outgrowth is initiated and thus modulate the process like in traumatic brain injury. These results open the door of a concomitant treatment at both sides of the lesion with RhoA inhibitor. However, we also pointed that RhoA inhibitor treatment led to an inhibition of several factors implicated in neurogenesis reflecting a global inhibition at term as detected in vivo that reached 2 weeks after treatment. RhoA inhibitor treatment is useful to initiate the neurogenesis process but needs to be supplied by a second treatment for increasing synaptic connections and the neuron reconnections.
2017-07-28 | PXD004639 | Pride
Project description:Rho family small GTPases serve as molecular switches in the regulation of diverse cellular functions including actin cytoskeleton remodeling, cell migration, gene transcription, and cell proliferation. Importantly, Rho overexpression is frequently seen in many carcinomas. However, published studies have almost invariably utilized immortal or tumorigenic cell lines to study Rho GTPase functions and there are no studies on the potential of Rho small GTPase to overcome senescence checkpoints and induce preneoplastic transformation of human mammary epithelial cells (hMECs). We found that ectopic expression of wild-type RhoA as well as a constitutively-active RhoA mutant (G14V) in primary hMEC strains led to their immortalization and preneoplastic transformation. Significantly, RhoA-T37A mutant, known to be incapable of interacting with many well known Rho-effectors ,was also capable of immortalizing hMECs.Our results demonstrate that RhoA can induce the preneoplastic transformation of hMECs by altering multiple pathways linked cellular transformation and breast cancer. Through microarray analysis, we want to identify genes and pathways linked to RhoA induced hMECs immortalization. Experiment Overall Design: 4 samples, in triplicate analyses per sample.
2008-10-26 | E-GEOD-12917 | biostudies-arrayexpress
Project description:Using mice with a keratinocyte-restricted deletion of the RhoA gene, we explored its role in the regulation of gene expression in vivo and in vitro RNA was isolated from RhoA-null or wildtype keratinocytes, in two different conditions, freshly isolated (in vivo) or cultured (in vitro), using the RNeasy kit (Qiagen, Germany). Hybridization to GeneChip Mouse Genome 430 2.0 Array (Affymetrix, Santa Clara, CA) was carried out at the Copenhagen University Hospital Microarray Center using standard protocols. 2 biological replicates were analyzed for each in vivo genotype (2 samples from RhoA-null, 2 from wildtype), while 3 replicates for each in vitro genotype.
2015-01-07 | E-GEOD-64714 | biostudies-arrayexpress
Project description:The small GTPase RhoA regulates a variety of cellular processes, including cell motility, proliferation, survival and permeability. In addition, there are reports suggesting that the RhoA-ROCK axis plays a role in VEGF-mediated angiogenesis, whereas other work has shown opposite effects. To elucidate this conflicting data, we examined HUVEC and HCAEC after stable overexpression (lentiviral transduction) of constitutively active (G14V/Q63L), dominant-negative (T19N), or wild-type RhoA using a variety of in vitro angiogenesis assays (proliferation, migration, tube formation, angiogenic sprouting, endothelial cell viability) and a HUVEC xenograft assay in immune incompetent NSGTM mice in vivo. We observed that expression of active as well as wild-type RhoA but not expression of dominant-negative RhoA significantly increased endothelial cell death as well as inhibited endothelial cell proliferation, migration, tube formation and angiogenic sprouting of endothelial cells in vitro and reduced HUVEC-related angiogenesis in vivo. Inhibition of RhoA by C3 transferase antagonized inhibitory RhoA effects and strongly enhanced VEGF-induced angiogenic sprouting in control-treated cells. In contrast, inhibition of RhoA effectors ROCK1/2 and LIMK1/2 had no significant effect on RhoA-related effects, but again increased angiogenic sprouting and migration of control-treated cells. In line with these data, VEGF did not activate RhoA in HUVEC as measured by a FRET-based biosensor. Furthermore, global transcriptome and subsequent bioinformatic gene ontology (GO) enrichment analyses revealed that constitutively active RhoA induces a differentially expressed gene pattern that is enriched for GO biological process terms such as mitotic nuclear division, cell proliferation, cell motility and cell adhesion and includes a significant decrease in VEGFR-2 and NOS3 expression. Thus, our data demonstrate that increased RhoA activity has the potential to trigger endothelial dysfunction and anti-angiogenic effects independently of its well-characterized downstream effectors ROCK and LIMK.
2022-07-06 | GSE182806 | GEO
Project description:Rho family small GTPases serve as molecular switches in the regulation of diverse cellular functions including actin cytoskeleton remodeling, cell migration, gene transcription, and cell proliferation. Importantly, Rho overexpression is frequently seen in many carcinomas. However, published studies have almost invariably utilized immortal or tumorigenic cell lines to study Rho GTPase functions and there are no studies on the potential of Rho small GTPase to overcome senescence checkpoints and induce preneoplastic transformation of human mammary epithelial cells (hMECs). We found that ectopic expression of wild-type RhoA as well as a constitutively-active RhoA mutant (G14V) in primary hMEC strains led to their immortalization and preneoplastic transformation. Significantly, RhoA-T37A mutant, known to be incapable of interacting with many well known Rho-effectors ,was also capable of immortalizing hMECs.Our results demonstrate that RhoA can induce the preneoplastic transformation of hMECs by altering multiple pathways linked cellular transformation and breast cancer. Through microarray analysis, we want to identify genes and pathways linked to RhoA induced hMECs immortalization.
2008-09-26 | GSE12917 | GEO
Project description:The study of dominantly heritable cancers has provided insights about tumor development. Gorlin syndrome (GS) is an autosomal dominant disorder wherein affected individuals develop multiple basal cell carcinomas (BCCs) of the skin. We developed a murine model of Ptch1 haploinsufficiency on an ornithine decarboxylase (ODC) transgenic background (Ptch1+/-/ODCt/C57BL/6) that is more sensitive to BCCs growth as compared with Ptch1+/+/ODCt/C57BL/6 littermates. Ptch1+/-/ODCt/C57BL/6 mice show an altered metabolic landscape in the phenotypically normal skin, including restricted glucose availability, restricted ribose/deoxyribose flow and NADPH production, an accumulation of α-ketoglutarate, aconitate, and citrate that is associated with reversal of the tricarboxylic acid cycle, coupled with increased ketogenic/lipogenic activity via acetyl-CoA, 3-hydroybutyrate, and cholesterol metabolites. Also apparent was an increased content/acetylation of amino-acids, glutamine and glutamate, in particular. Accordingly, metabolic alterations due to a single copy loss of Ptch1 in Ptch1+/-/ODCt/C57BL/6 heterozygous mice may provide insights about the cancer prone phenotype of BCCs in GS patients, including biomarkers/targets for early intervention.
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