TSC2 loss in neural progenitor cells suppresses mRNA translation of neurodevelopmental genes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1164315 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30775615_1.fastq.gz | Fastqsanger.gz | |||
| SRR30775615_2.fastq.gz | Fastqsanger.gz | |||
| SRR30775616_1.fastq.gz | Fastqsanger.gz | |||
| SRR30775616_2.fastq.gz | Fastqsanger.gz | |||
| SRR30775617_1.fastq.gz | Fastqsanger.gz |
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Project description:Tuberous sclerosis complex (TSC) is an inherited neurodevelopmental (ND) disorder with frequent manifestations of epilepsy and autism spectrum disorder (ASD) caused by mutations in TSC1 or TSC2 genes. TSC1 and TSC2 form a complex inhibiting mechanistic target of rapamycin complex-1 (mTORC1) signaling, leading to hyperactive mTORC1 signaling upon TSC1/2 loss of function. Although rapalogs, which are FDA-approved allosteric mTORC1-selective inhibitors, are used to treat TSC-associated hamartomas, they are not effective for treating ND manifestations. mTORC1 signaling controls protein synthesis by regulating formation of the eIF4F complex, whose activity is further modulated by the MNK1/2 kinases via phosphorylation of the eIF4F subunit eIF4E. While both these pathways modulate translation in transcript-selective fashion depending on features in target mRNAs’ 5’ untranslated regions (5’UTRs), their effect on transcriptome-wide patterns of mRNA translation has not been compared. Here, employing CRISPR-modified, isogenic TSC2 patient-derived neural progenitor cells (NPCs), we examined how loss of TSC2 affects gene expression via changes in mRNA abundance and translation at a transcriptome-wide scale. This revealed abundant mRNA translation alterations in TSC2-Null NPCs overlapping with those we previously observed in TSC1-Null NPCs. Surprisingly, numerous non-monogenic ASD- and NDD-associated genes, identified in patients harboring putative loss-of-function mutations, were selectively translationally suppressed in TSC2-Null NPCs consistent with their distinct repertoire of 5’UTR features. Importantly, translation of these ASD- and NDD-associated genes was reversed upon inhibition of either mTORC1 or MNK1/2 signaling using RMC-6272 or eFT-508, respectively. This study thereby establishes mTORC1-eIF4F and MNK-eIF4E-sensitive mRNA translation as key components in TSC, ASD and other neurodevelopmental disorders; and lay the groundwork for evaluating drugs in clinical development that target these pathways as a treatment strategy for TSC as well as ASD/NDD.
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Project description:Multipotent neural stem cells (NSCs) that reside within the ventricular-subventricular zone (V-SVZ) of the brain generate a variety of cell types. Here we provide transcriptomes of NSCs that have lost Tsc2 as occurs in the neurodevelopmental disorder Tuberous Sclerosis Complex (TSC).
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Project description:Multipotent neural stem cells (NSCs) that reside within the ventricular-subventricular zone (V-SVZ) of the brain generate a variety of cell types. Here we provide transcriptomes of NSCs that have lost Tsc2 as occurs in the neurodevelopmental disorder Tuberous Sclerosis Complex (TSC).
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Project description:Multipotent neural stem cells (NSCs) that reside within the ventricular-subventricular zone (V-SVZ) of the brain generate a variety of cell types. Here we provide transcriptomes of cells that have lost Tsc2 as occurs in the neurodevelopmental disorder Tuberous Sclerosis Complex (TSC).
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Project description:Human Tsc1 and Tsc2 genes predispose to Tuberous Sclerosis Complex (TSC), a disorder characterized by the widespread of benign tumors. Tsc1 and Tsc2 proteins form a complex and serve as a GAP (GTP activating protein) for Rheb, a GTPase regulating a downstream kinase, mTor. The fission yeast genome contains tsc1+ and tsc2+, homologs of human Tsc1and Tsc2, respectively. In this study we analyzed gene expression profile in a genome-wide scale and found that deletion of either tsc1+ or tsc2+ affects gene induction upon nitrogen starvation. Three hours after nitrogen depletion genes encoding permeases and genes required for meiosis are less induced. Under the same condition, retrotransposons, G1-cyclin (pas1+) and a gene normally repressed by glucose (inv1+) are more induced. We also demonstrate that a mutation (cpp1-1) in a gene encoding aβ-subunit of a farnesyl transferase can suppress most of the phenotypes associated with deletion of tsc1+ or tsc2+. When a mutant of rhb1+ (homolog of human Rheb), which bypasses the requirement of protein farnesylation, was expressed, the cpp1-1 mutation could no longer suppress, indicating that deficient farnesylation of Rhb1 contributes to the suppression. Based on these results, we discuss the TSC-pathology and possible improvement in chemotherapy for TSC. Keywords: Keywards: Nitrogen starvation, Dtsc1. Dtsc2
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Project description:Transcriptome analysis of the heads of 5 dpf epdc5-/-, tsc2-/-, depdc5-/- x tsc2-/- and wildtype zebrafish larvae to provide insights into the neuropathological processes underlying the observed epileptic phenotype in sv2a-/- zebrafish larvae.
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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.
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