Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Loss of Tsc1 in cerebellar Purkinje cells induces transcriptional and translation changes in FMRP target transcripts

ABSTRACT: Tuberous sclerosis complex (TSC) is a genetic disorder that is associated with multiple neurological manifestations. Previously, we demonstrated that Tsc1 loss in cerebellar Purkinje cells (PCs) can cause altered social behavior in mice. Here, we performed detailed transcriptional and translational analyses of Tsc1-deficient PCs to understand the molecular alterations in these cells. We found that target transcripts of the Fragile X Mental Retardation Protein (FMRP) are reduced in mutant PCs with evidence of increased degradation. Surprisingly, we observed unchanged ribosomal binding for many of these genes using Translating Ribosome Affinity Purification (TRAP). Finally, we found that the FMRP target, SHANK2, was reduced in PC synapses, suggesting that compensatory increases in ribosomal binding efficiency may be unable to overcome reduced transcript levels. These data further implicate dysfunction of FMRP and its targets in TSC and suggest that treatments aimed at restoring the function of these pathways may be beneficial.

ORGANISM(S): Mus musculus

PROVIDER: GSE169719 | GEO | 2021/07/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Drosophila S2R+ / TSC1 / TSC2 mutant phosphoproteomics

Project description:The tuberous sclerosis complex (TSC) family of tumor suppressors, TSC1 and TSC2, function together in an evolutionarily conserved protein complex that is a point of convergence for major cell signaling pathways that regulate mTOR complex 1 (mTORC1). Mutation or aberrant inhibition of the TSC complex is common in various human tumor syndromes and cancers. The discovery of novel therapeutic strategies to selectively target cells with functional loss of this complex is therefore of substantial clinical relevance to TSC and sporadic cancers. We developed a CRISPR-based method to generate homogenous mutant Drosophila cell lines. By combining TSC1 and TSC2 mutant cell lines with RNAi screens against all kinases and phosphatases, we identified synthetic interactions with TSC1 and TSC2. Knockdown of three candidate genes (mRNA-cap, Pitslre and CycT; orthologs of RNGTT, CDK11 and CCNT1 in humans) reduced the population growth rate of both Drosophila TSC1 and TSC2 mutant cells but not that of wild-type cells. Moreover, knockdown of all three genes displayed similar selective effects in mammalian TSC2-deficient cell lines, including human tumor-derived cells, illustrating the power of this cross species screening strategy to identify potential drug targets.

2018-10-24 | PXD002670 | Pride

Transcriptome analysis of TSC1 and TSC2 using Nanopore long-read sequencer

Project description:Tuberous sclerosis complex (TSC) is a relatively common autosomal dominant disorder characterized by multiple dysplastic organ lesions and neuropsychiatric symptoms, caused by loss-of-function mutation of either TSC1 or TSC2. Target-capture full-length double-stranded cDNA sequencing using long-read sequencer Nanopore (Nanopore Long-read Target Sequencing) revealed that the various kinds of the TSC1 and TSC2 full-length transcripts and the novel intron retention transcripts of TSC2 in TSC patient. Our results indicate that the Nanopore Long-read Target Sequencing is useful for the detection of mutations and confers information on the full-length alternative splicing transcripts for the genetic diagnosis.

2023-09-04 | GSE241410 | GEO

Tuberous sclerosis complex 1 (Tsc1) enforces quiescence of naive T cells to promote immune homeostasis and function

Project description:The mechanisms that regulate T cell quiescence are poorly understood. We report that tuberous sclerosis complex 1 (Tsc1) establishes a quiescent program in naïve T cells by controlling cell size, cell cycle entry, and responses to T cell receptor stimulation. Loss of quiescence predisposed Tsc1-deficient T cells to apoptosis that depleted conventional T cells and invariant natural killer T cells. Loss of Tsc1 function dampened in vivo immune responses to bacterial infection. Tsc1-deficient T cells exhibited increased mTORC1 but diminished mTORC2 activities, with mTORC1 activation essential for the disruption of immune homeostasis. Therefore, Tsc1-dependent control of mTOR is crucial in establishing naïve T cell quiescence to facilitate adaptive immune function. Naïve CD4 and CD8 T cells from wild-type and Tsc1-deficient mice (in triplicates each group) were stimulated with or without TCR signaling. RNA was analyzed by microarrays. WT/KO for 0 and 4 hr for CD4 (triplicates), and WT/KO for 0 hr for CD8 (duplicates).

2011-07-11 | E-GEOD-29797 | biostudies-arrayexpress

Regulation of PERK-eIF2Î± Signaling by Tuberous Sclerosis Complex-1 Controls Homeostasis and Survival of Myelinating Oligodendrocytes

Project description:Tuberous sclerosis complex (TSC), an autosomal dominant disorder caused by mutations in either TSC1 or TSC2, exhibits white matter abnormalities including CNS myelin deficits. however, underlying mechanisms are not fully understood. Here we find that, unexpectedly, constitutive activation of mTOR signaling caused by Tsc1 deletion in the oligodendrocyte lineage results in severe myelination defects and oligodendrocyte cell death. Expression profiling analysis reveals that Tsc1 ablation induces prominent endoplasmic reticulum (ER) stress responses through the PERKâeIF2Î± dependent signaling axis and activates Fas-JNK apoptotic pathways. Our studies suggest that TSC1-mTOR signaling acts as an important checkpoint for maintaining oligodendrocyte homeostasis. Gene expression profiling of optic nerve from P12 control and Tsc1cKO mice

2016-07-22 | E-GEOD-74893 | biostudies-arrayexpress

Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs

Project description:Memory CD8+ T cells are an essential component of protective immunity. Signaling via mechanistic target of rapamycin (mTOR) has been implicated in the regulation of the differentiation of effector and memory T cells. However, little is understood about the mechanisms that control mTOR activity, or the effector pathways regulated by mTOR, in this process. We describe here that tuberous sclerosis 1 (Tsc1), a regulator of mTOR signaling, plays a crucial role in promoting the differentiation and function of memory CD8+ T cells in response to Listeria monocytogenes infection. Mice with specific deletion of Tsc1 in antigen-experienced CD8+ T cells evoked normal effector responses, but were markedly impaired in the generation of memory T cells and their recall responses to antigen re-exposure in a cell-intrinsic manner. Tsc1 deficiency suppressed the generation of memory-precursor effector cells (MPECs) while promoting short-lived effector cell (SLEC) differentiation. Functional genomic analysis indicated that Tsc1 coordinated gene expression programs underlying immune function, transcriptional regulation and cell metabolism. Furthermore, Tsc1 deletion led to excessive mTORC1 activity and dysregulated cellular metabolism including glycolytic and oxidative metabolism. These findings establish a Tsc1-mediated checkpoint in linking immune signaling and cell metabolism to orchestrate memory CD8+ T cell development and function. We used microarrays to explore the gene expression profiles differentially expressed in OVA-specific CD8+ T-cells from wild-type (WT; Tsc1-fl/fl and cre-negative) and Tsc1-/- (Tsc1-fl/fl and Granzyme B-cre-positive) mice

2014-09-20 | E-GEOD-61591 | biostudies-arrayexpress

SILAC APMS analysis of GFP tagged TSC2 in Hela Cells

Project description:HSP90 and its co-chaperon R2TP are involved to assemble and stabilize many macro-molecular complexes involved in cell proliferation. R2TP complex is composed of RUVBL1 and RUVBL2 AAA+ ATPases and two adapter proteins RPAP3 and PIH1D1. The N-terminal domain of PIH1D1 was described to possess a basic pocket that binds phosphorylated peptides on some of the R2TP clients. Subunits of TSC complex (Tuberous SClerosis) have previously been described in proteomic analysis of proteins immune-precipitated with PIH1D1 N-terminal domain. TSC complex is a regulator of mTOR activity. It is composed of TSC1, TSC2 and TBC1D7 subunits. Here, we show that (i) TSC1 and TSC2 are both substrates of HSP90, (ii) the HSP90/R2TP system has multiple interaction with TSC complex subunits and (iii) it is functionally involved in the assembly of the TSC complex. We found a direct interaction of TSC1 with the phospho-binding pocket of PIH1D1 N-terminal domain regardless of phosphorylationbut in a non-canonical phosphorylation independent manner[XM1] . TSC2 and TBC1D7 would also interact with R2TP but independently of PIH1D1. Taken together, these data suggest that R2TP acts as a platform for the independent recruitment of TSC subunits before the assembly of the TSC complex

2024-11-12 | PXD030402 | Pride

Proteogenomic characterization of developmental defects in the forebrain resulting from hyperactivated mTOR signaling

Project description:Hyperactivated mTOR signaling in the developing brain by mutation of TSC1 genes has multiple forms of pathology including tuberous sclerosis complex (TSC). To examine the downstream networks affected in the developing brain by hyperactivated mTOR signaling, we performed an integrated analysis of transcriptomic and proteomic analysis of forebrain of wild-type and TSC1/Emx1-Cre mouse. Our results provide novel and fundamental molecular bases for understanding hyperactivaed mTOR signaling-induced brain defects which can in turn facilitate identification of potential diagnostic markers and therapeutic targets for mTOR signaling-related neurological disorders.

2018-08-16 | PXD005768 | Pride

Timecourse of epileptogenesis in an TSC1 inducible mouse model

Project description:To determine how the loss of TSC induces epileptogenesis, we made use of an inducible Tsc1 knock-out mouse model. Tsc1 was homozygously deleted in all CAMK2A positive neurons. Hippocampal tissue was collected at different time points after gene deletion and during epileptogenesis, of mice of both sexes. Also, mice treated with 10mg/kg rapamycin were included in the experiment. Using RNA-seq analysis, we identified differentially expressed genes encoding either ion channel and/or genes belonging to the GO-term ‘action potential’. Of these genes, 50% were already significantly dysregulated before or just around seizure onset, suggesting that these genes could be driver genes of epileptogenesis. Of the genes encoding ion channels or belonging to the Gene Ontology term action potential, 27 were differentially expressed just before seizure onset, suggesting a potential driving role in epileptogenesis. Our data highlight the complex changes driving epileptogenesis in TSC, including the changed expression of multiple ion channels. Our study emphasizes inhibition of the TSC/mTOR signaling pathway as a promising therapeutic approach to target epilepsy in patients with TSC.

2021-11-11 | GSE164306 | GEO

Rapamycin and dexamethasone during pregnancy prevents tuberous sclerosis complex associated cystic kidney disease

Project description:Chronic kidney disease is the main cause of mortality in patients with tuberous sclerosis complex disease (TSC). The mechanisms underlying TSC cystic kidney disease remain unclear with no available interventions to prevent cyst formation. Using targeted deletion of TSC1 in nephron progenitor cells, we showed that cysts in TSC1 null embryonic kidneys originate from injured proximal tubular cells with high mTOR complex 1 activity. Injection of rapamycin to pregnant mice inhibited the mTOR pathway and tubular cell proliferation in kidneys of TSC1 null offspring. Rapamycin also prevented renal cystogenesis and prolonged the life span of TSC newborns. Gene expression analysis of proximal tubule cells, identified sets of genes and pathways that were modified secondary to TSC1 deletion and rescued by rapamycin administration during nephrogenesis. Inflammation with mononuclear infiltration was observed in the cystic areas of TSC1 null kidneys. Dexamethasone administration during pregnancy decreased cyst formation not only by inhibiting the inflammatory response but also by interfering with the mTORC1 pathway. These results reveal novel mechanisms of cystogenesis in TSC disease and suggest new interventions prior to birth to ameliorate cystic disease in offspring.

2020-06-10 | GSE152165 | GEO

Tuberous sclerosis complex renal lesion pleiotropy arises from multiple aberrant developmental processes

Project description:Tuberous sclerosis complex (TSC) is a multisystem tumor-forming disorder caused by loss of TSC1 or TSC2. Renal manifestations predominately include cysts and angiomyolipomas. Despite a well-described monogenic etiology, the cellular pathogenesis has remained elusive. Here, we report a novel genetically-engineered human renal organoid model which recapitulates pleiotropic features of TSC kidney disease in vitro and upon orthotopic xenotransplantation. We find that loss of TSC1/2 affects multiple developmental processes in the renal epithelial, stromal, and glial compartments. First, loss of TSC1/2 leads to an expanded stroma by favouring stromal cell fate acquisition and alters terminal stromal cell identity. Second, epithelial cells in the TSC1/2-/- organoids exhibit a rapamycin-insensitive epithelial-to-mesenchymal transition. Third, a melanocytic population forms exclusively in TSC1/2-/- organoids, branching from MITF+ Schwann cell precursors of a bona fide neural crest-to-Schwann cell differentiation trajectory. Together, these results illustrate the pleiotropic developmental consequences of biallelic inactivation of TSC1/2 and offer insight into the pathogenesis of TSC kidney lesions.

2022-07-05 | GSE182632 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data