Tuberous sclerosis complex-associated CNS abnormalities depend on hyperactivation of mTORC1 and Akt
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA430419 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6500970.fastq.gz | Fastqsanger.gz | |||
| SRR6500971.fastq.gz | Fastqsanger.gz | |||
| SRR6500972.fastq.gz | Fastqsanger.gz | |||
| SRR6500973.fastq.gz | Fastqsanger.gz | |||
| SRR6500974.fastq.gz | Fastqsanger.gz |
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Project description:Tuberous sclerosis complex (TSC) is a dominantly inherited disease, caused by hyperactivation of the mTORC1 pathway and characterized by the development of hamartomas and benign tumors, also in the brain. Among the neurological manifestations associated with TSC, the tumor progression of static subependymal nodules (SENs) into subependymal giant cell astrocytomas (SEGAs) is one of the major causes of morbidity and shortened life expectancy. To date, mouse modeling has failed in reproducing these two lesions. Here we report that simultaneous hyperactivation of mTORC1 and Akt pathways by co-deletion of Tsc1 and Pten, selectively in postnatal neural stem cells (pNSCs), is required for the formation of bona fide SENs and SEGAs. Notably, both lesions closely recapitulate the pathognomonic morphological and molecular features of the corresponding human abnormalities. The establishment of long-term expanding pNSC lines from mouse SENs and SEGAs made possible the identification of mTORC2 as one of the mediators conferring tumorigenic potential to SEGA pNSCs. Of note, in spite of concurrent Akt hyperactivation in mouse brain lesions, single mTOR inhibition by rapamycin was sufficient to strongly impair mouse SEGA growth. This study provides the first evidence that, concomitant with mTORC1 hyperactivation, sustained activation of Akt and mTORC2 in pNSCs is a mandatory step for the induction of SENs and SEGAs and, at the same time, makes available an unprecedented NSC-based in vivo/in vitro model to be exploited for identifying actionable targets in TSC.
2018-02-14 | GSE109321 | GEO
Project description:Tuberous Sclerosis Complex (TSC) is caused by germline TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and tumors in multiple organs including the brain, heart, lung (lymphangioleiomyomatosis), and kidney (angiomyolipoma and renal cell carcinoma). Previously, we found that TFEB is constitutively active in models of TSC. To determine the impact of TFEB in vivo, we generated two novel mouse models of TSC, resulting in premature death, in which kidney pathology was the primary phenotype. RNA sequencing revealed that lysosomal and proteasomal gene pathways were the most highly upregulated in the TSC2-deficient kidneys. Knockout of TFEB rescued both kidney pathology and overall survival in both models, indicating that TFEB is the primary driver of renal disease in TSC. Importantly, mTORC1 activity, which was elevated in the TSC2 knockout kidneys, was normalized by TFEB knockout. Knockdown of Rheb or treatment of TSC2-deficient cells with Rapamycin paradoxically increases TFEB phosphorylation at the mTORC1-site (S211) and relocalizes TFEB from the nucleus to the cytoplasm via a Rag-dependent mechanism. Accordingly, treatment of TSC2 knockout mice with Rapamycin normalized lysosomal gene expression, similar to TFEB knockout, suggesting that the beneficial effects of Rapamycin in TSC are TFEB-dependent. These results change the view of the mechanisms leading to mTORC1 hyperactivation in TSC and may lead to novel therapeutic avenues for the treatment of TSC.
2023-09-28 | GSE244072 | GEO
Project description:TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex
| PRJNA1021195 | ENA
Project description:Tuberous sclerosis complex (TSC) is a dominantly inherited disease caused by hyperactivation of the mTORC1 pathway and characterized by the development of hamartomas and benign tumors, including in the brain. Among the neurological manifestations associated with TSC, the tumor progression of static subependymal nodules (SENs) into subependymal giant cell astrocytomas (SEGAs) is one of the major causes of morbidity and shortened life expectancy. To date, mouse modeling has failed in reproducing these 2 lesions. Here we report that simultaneous hyperactivation of mTORC1 and Akt pathways by codeletion of Tsc1 and Pten, selectively in postnatal neural stem cells (pNSCs), is required for the formation of bona fide SENs and SEGAs. Notably, both lesions closely recapitulate the pathognomonic morphological and molecular features of the corresponding human abnormalities. The establishment of long-term expanding pNSC lines from mouse SENs and SEGAs made possible the identification of mTORC2 as one of the mediators conferring tumorigenic potential to SEGA pNSCs. Notably, in spite of concurrent Akt hyperactivation in mouse brain lesions, single mTOR inhibition by rapamycin was sufficient to strongly impair mouse SEGA growth. This study provides evidence that, concomitant with mTORC1 hyperactivation, sustained activation of Akt and mTORC2 in pNSCs is a mandatory step for the induction of SENs and SEGAs, and, at the same time, makes available an unprecedented NSC-based in vivo/in vitro model to be exploited for identifying actionable targets in TSC.
| S-EPMC5873854 | biostudies-literature
Project description:Tuberous Sclerosis Complex (TSC) is caused by variants in either TSC1 or TSC2, which cooperate to inhibit the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with neurological disorders that have been attributed to disinhibition of mTORC1, but mechanisms connecting dysregulation of mTORC1 to molecular and physiological changes in neurons remain unclear. In this study, we sought to understand transcriptional changes in TSC and identified down-regulation of the immediate early gene, EGR1, in TSC2-deficient excitatory neurons. Furthermore, we found that activity-dependent transcription is impaired in TSC due to abnormalities in epigenetic maturation. Finally, we determined that mTORC1 inhibition started late in neuronal maturation of human neurons is only partially effective in reversing gene expression changes and ineffective in reducing spontaneous neuronal hyperactivity in TSC. These data demonstrate a critical window in early brain development where mTORC1 dysregulation leads to epigenetic changes that contribute to persistent neuronal abnormalities.
2025-10-25 | GSE286912 | GEO
Project description:Tuberous Sclerosis Complex (TSC) is caused by variants in either TSC1 or TSC2, which cooperate to inhibit the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with neurological disorders that have been attributed to disinhibition of mTORC1, but mechanisms connecting dysregulation of mTORC1 to molecular and physiological changes in neurons remain unclear. In this study, we sought to understand transcriptional changes in TSC and identified down-regulation of the immediate early gene, EGR1, in TSC2-deficient excitatory neurons. Furthermore, we found that activity-dependent transcription is impaired in TSC due to abnormalities in epigenetic maturation. Finally, we determined that mTORC1 inhibition started late in neuronal maturation of human neurons is only partially effective in reversing gene expression changes and ineffective in reducing spontaneous neuronal hyperactivity in TSC. These data demonstrate a critical window in early brain development where mTORC1 dysregulation leads to epigenetic changes that contribute to persistent neuronal abnormalities.
2025-10-25 | GSE286949 | GEO
Project description:As an evolutionarily conserved master regulator of metabolism, mechanistic target of rapamycin complex 1 (mTORC1) regulates cell states and fates in development, cancer and aging. mTORC1 activity regulation was critical for pluripotent stem cells maintenance and cell fate transitions. Inhibition of mTORC1 induces embryonic stem cells (ESCs) entry into a paused state which reversibly arrests self-renewal leaving pluripotency intact. Hyperactivation of mTORC1 impedes both pluripotency re-establishment and exit of PSCs. As shown that mTORC1 mediates TFE3 nuclear translocation block pluripotency exit, whether similar mechanisms through transcription factor TFE3 are involved in these processes, and the detailed mechanism by which mTORC1-TFE3 regulates critical transcriptional processes for these transitions, remain unclear. In this study, we demonstrate that the nuclear translocation of TFE3, induced by hyperactivation of mTORC1, results in its binding to the nucleosome remodeling and deacetylation (NuRD) complex in both re-establishment and exit of pluripotency. This interaction inhibits the expression of various crucial genes during different fate transitions of PSCs. Our findings uncover a common and key role of TFE3-NuRD association as mediator of mTORC1 to block pluripotent cell fate transitions, with implications for various fields including physiological and pathological diseases.
2025-07-09 | GSE301743 | GEO
Project description:As an evolutionarily conserved master regulator of metabolism, mechanistic target of rapamycin complex 1 (mTORC1) regulates cell states and fates in development, cancer and aging. mTORC1 activity regulation was critical for pluripotent stem cells maintenance and cell fate transitions. Inhibition of mTORC1 induces embryonic stem cells (ESCs) entry into a paused state which reversibly arrests self-renewal leaving pluripotency intact. Hyperactivation of mTORC1 impedes both pluripotency re-establishment and exit of PSCs. As shown that mTORC1 mediates TFE3 nuclear translocation block pluripotency exit, whether similar mechanisms through transcription factor TFE3 are involved in these processes, and the detailed mechanism by which mTORC1-TFE3 regulates critical transcriptional processes for these transitions, remain unclear. In this study, we demonstrate that the nuclear translocation of TFE3, induced by hyperactivation of mTORC1, results in its binding to the nucleosome remodeling and deacetylation (NuRD) complex in both re-establishment and exit of pluripotency. This interaction inhibits the expression of various crucial genes during different fate transitions of PSCs. Our findings uncover a common and key role of TFE3-NuRD association as mediator of mTORC1 to block pluripotent cell fate transitions, with implications for various fields including physiological and pathological diseases.
2024-08-13 | GSE274330 | GEO
Project description:As an evolutionarily conserved master regulator of metabolism, mechanistic target of rapamycin complex 1 (mTORC1) regulates cell states and fates in development, cancer and aging. mTORC1 activity regulation was critical for pluripotent stem cells maintenance and cell fate transitions. Inhibition of mTORC1 induces embryonic stem cells (ESCs) entry into a paused state which reversibly arrests self-renewal leaving pluripotency intact. Hyperactivation of mTORC1 impedes both pluripotency re-establishment and exit of PSCs. As shown that mTORC1 mediates TFE3 nuclear translocation block pluripotency exit, whether similar mechanisms through transcription factor TFE3 are involved in these processes, and the detailed mechanism by which mTORC1-TFE3 regulates critical transcriptional processes for these transitions, remain unclear. In this study, we demonstrate that the nuclear translocation of TFE3, induced by hyperactivation of mTORC1, results in its binding to the nucleosome remodeling and deacetylation (NuRD) complex in both re-establishment and exit of pluripotency. This interaction inhibits the expression of various crucial genes during different fate transitions of PSCs. Our findings uncover a common and key role of TFE3-NuRD association as mediator of mTORC1 to block pluripotent cell fate transitions, with implications for various fields including physiological and pathological diseases.
2024-08-13 | GSE274328 | GEO
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