Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJDB19710 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Schizophrenia is a highly heritable psychiatric disorder, yet the molecular mechanisms by which genetic risk contributes to disease pathophysiology remain largely unknown. In this study, we investigate the functional consequences of XPO7 loss of function (LoF) in human induced pluripotent stem cell (iPSC)-derived neurons, focusing on its role as a schizophrenia risk gene identified through recent large-scale exome sequencing analyses. By integrating high-precision electrophysiological measurements with transcriptomic, proteomic, and imaging approaches, we demonstrate that XPO7 LoF alters Na+ channel properties and availability, disrupts neuronal excitability, and impairs the synchrony and regularity of network activity. These functional deficits are accompanied by widespread molecular dysregulation affecting nucleocytoplasmic transport, ion channel function, and synaptic composition. Among the dysregulated proteins is Nav1.2, a voltage-gated sodium channel encoded by the schizophrenia-associated gene SCN2A, which exhibits aberrant subcellular distribution in XPO7 LoF neurons, characterized by increased somatic accumulation and reduced synaptic localization. Together, these findings position XPO7 as a critical regulator of neuronal excitability and connectivity, linking channelopathy to cellular phenotypes relevant to schizophrenia pathophysiology.
2026-04-09 | GSE301134 | GEO
Project description:Cargo molecules which exceed the passive diffusion limit of ~5nm require active translocation to cross the nuclear pore complex (NPC). Such a facilitated transport is achieved by specialized nuclear transport receptors (NTRs), which are classified according to their shuttling direction. Exportins bind their cargo in a RanGTP-dependent manner inside the nucleus and release it in the cytoplasm. Importins, on the other hand, bind their cargo without RanGTP and transfer it in the opposite direction. CRM1/Xpo1 is one of the best-characterized NTRs mostly due to the availability of specific inhibitors, like leptomycin B, which allowed cargo validation in vivo. Such inhibitors have not been characterized for other NTRs, thus analysis of those lagged behind. Here, we developed nanobodies to specifically target exportin 7/Xpo7 and block its transport pathway. Moreover, in-depth MS/MS analysis of Xpo7 under nuclear (+RanGTP) and cytoplasmic conditions (-RanGTP) revealed novel binders including ~200 potential export substrates, but also ~30 nuclear import cargoes. Enrichment factors of a putative cargo were calculated using the iBAQ strategy to quantify detectable proteins in the input as well as in the import or export mimicking material. Validation of selected cargo molecules was then accomplished by anti-Xpo7 nanobodies causing cargo mislocalization when transfected into cultured cells. Collectively, the data establish Xpo7 as a bidirectional NTR with a broad substrate specificity.
2018-05-07 | PXD008746 | Pride
Project description:Mutation of TP53, a tumor suppressor in cancer, is common and leads to extremely poor prognosis. To identify vulnerabilities in TP53-mutated tumors, we performed genome-wide CRISPR/Cas9 screens using isogenic Trp53 wild-type and knockout mouse acute myeloid leukemia (AML) lines. Here, we show that histone gene regulation governed by the XPO7-NPAT pathway is essential for survival of TP53-mutated AML cells. In TP53 wild-type cells, XPO7 enhances p53 nuclear localization and functions as a tumor suppressor, but in TP53-mutated cells, XPO7 promotes cell proliferation by retaining NPAT, a histone gene activator, in the nucleus. NPAT depletion led to genome-wide histone loss, enhancing vulnerability to genotoxic stress. Human AML cases show predominant expression of XPO7 and NPAT when TP53 is mutated, suggesting a potential therapeutic vulnerability.
2026-04-22 | GSE264595 | GEO
Project description:Mutation of TP53, a tumor suppressor in cancer, is common and leads to extremely poor prognosis. To identify vulnerabilities in TP53-mutated tumors, we performed genome-wide CRISPR/Cas9 screens using isogenic Trp53 wild-type and knockout mouse acute myeloid leukemia (AML) lines. Here, we show that histone gene regulation governed by the XPO7-NPAT pathway is essential for survival of TP53-mutated AML cells. In TP53 wild-type cells, XPO7 enhances p53 nuclear localization and functions as a tumor suppressor, but in TP53-mutated cells, XPO7 promotes cell proliferation by retaining NPAT, a histone gene activator, in the nucleus. NPAT depletion led to genome-wide histone loss, enhancing vulnerability to genotoxic stress. Human AML cases show predominant expression of XPO7 and NPAT when TP53 is mutated, suggesting a potential therapeutic vulnerability.
2026-04-22 | GSE264594 | GEO
Project description:Mutation of TP53, a tumor suppressor in cancer, is common and leads to extremely poor prognosis. To identify vulnerabilities in TP53-mutated tumors, we performed genome-wide CRISPR/Cas9 screens using isogenic Trp53 wild-type and knockout mouse acute myeloid leukemia (AML) lines. Here, we show that histone gene regulation governed by the XPO7-NPAT pathway is essential for survival of TP53-mutated AML cells. In TP53 wild-type cells, XPO7 enhances p53 nuclear localization and functions as a tumor suppressor, but in TP53-mutated cells, XPO7 promotes cell proliferation by retaining NPAT, a histone gene activator, in the nucleus. NPAT depletion led to genome-wide histone loss, enhancing vulnerability to genotoxic stress. Human AML cases show predominant expression of XPO7 and NPAT when TP53 is mutated, suggesting a potential therapeutic vulnerability.
2026-02-09 | GSE264596 | GEO
Project description:Genetic inactivation of serine racemase produces behavioral phenotypes related to schizophrenia in mice
| PRJNA110227 | ENA
Project description:To determine the transcriptional function (if any) of the presumed nuclear export protein Xpo7 or RanBP16 Murine fetal liver erythroid precursors (Ter119-negative cells) were isolated from C57Bl6 E14.5 embryos by magnetic depletion and infected with retroviruses containing shRNA constructs against Xpo7. They were then cultured in Epo-containing media (2U/mL) for 36hrs until they were fully differentiated and then sorted by FACS for GFP+ (infected) cells in order to isolate total RNA to be used for the profiling. Expression profiling in late cultured mouse erythroblasts before and after knockdown of gene Xpo7.
2014-01-29 | E-GEOD-54457 | biostudies-arrayexpress
Project description:Setd1a Insufficiency in Mice Attenuates Excitatory Synaptic Function and Recapitulates Schizophrenia-related behavioral abnormalities
| PRJDB10118 | ENA
Project description:Among the fundamental unresolved questions in psychiatry is why symptoms of psychosis, such as auditory hallucinations in schizophrenia, fail to appear until early adulthood. Here we report that in mouse models of 22q11.2 deletion syndrome (22q11DS), a leading genetic cause of schizophrenia, synaptic transmission at thalamocortical inputs to the auditory cortex becomes disrupted later in life, thereby recapitulating the adult onset of psychosis. Age-dependent disruption of thalamocortical synaptic transmission in 22q11DS is mediated by dopamine receptor Drd2-targeting microRNA miR-338-3p, which is enriched in the thalamus but becomes depleted due to haploinsufficiency of the microRNA-processing 22q11DS gene Dgcr8. Deletion/knockdown of miR-338-3p causes the Drd2 increase in the auditory thalamus and abnormal sensitivity of 22q11DS thalamocortical inputs to antipsychotics, replicates auditory synaptic and behavioral abnormalities in 22q11DS, and eliminates age dependence of these auditory deficits. These results suggest that miR-338-3p mediates the pathogenic mechanism of 22q11DS-related psychosis and controls its late onset.
2016-10-10 | GSE73981 | GEO
Project description:Mitochondrial function relies on the coordinated transcription of mitochondrial and nuclear genomes to assemble respiratory chain complexes. Across species, the SIN3 coregulator influences mitochondrial functions, but how its loss impacts mitochondrial homeostasis and metabolism in the context of a whole organism is unknown. Exploring this link is important because SIN3 haploinsufficiency causes intellectual disability/autism syndromes and SIN3 plays an important role in tumor biology. Here we show that loss of C. elegans SIN-3 results in transcriptional deregulation of mitochondrial- and nuclear-encoded mitochondrial genes, potentially leading to mito-nuclear imbalance. Consistent with impaired mitochondrial function, sin-3 mutants show extensive mitochondrial fragmentation by transmission electron microscopy (TEM) and in vivo imaging, and altered oxygen consumption. Metabolomic analysis of sin-3 mutant animals identifies a signature of mitochondria stress and deregulation of methionine flux, resulting in decreased S-adenosyl methionine (SAM) and increased polyamine levels. Our results identify SIN3 as a key regulator of mitochondrial dynamics and metabolic flux, with important implications for human pathologies.
2024-04-01 | MTBLS8439 | MetaboLights