Neural progenitors derived from Tuberous Sclerosis Complex patients exhibit attenuated PI3K/AKT signaling and delayed neuronal differentiation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA437467 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6819091_1.fastq.gz | Fastqsanger.gz | |||
| SRR6819091_2.fastq.gz | Fastqsanger.gz | |||
| SRR6819092_1.fastq.gz | Fastqsanger.gz | |||
| SRR6819092_2.fastq.gz | Fastqsanger.gz | |||
| SRR6819093_1.fastq.gz | Fastqsanger.gz |
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Project description:Tuberous Sclerosis Complex (TSC) is a disease caused by autosomal dominant mutations in the TSC1 or TSC2 genes, and is characterized by tumor susceptibility, brain lesions, seizures and behavioral impairments. The TSC1 and TSC2 genes encode proteins forming a complex (TSC), which is a major regulator and suppressor of mammalian target of rapamycin (mTOR) in complex 1 (mTORC1), a signaling complex that promotes cell growth and proliferation. TSC1/2 loss of heterozygosity (LOH) and the subsequent complete loss of TSC regulatory activity in null cells causes mTORC1 dysregulation and TSC-associated brain lesions or other tissue tumors. However, it is not clear whether TSC1/2 heterozygous brain cells are abnormal and contribute to TSC neuropathology. To investigate this issue, we generated induced pluripotent stem cells (iPSCs) from TSC patients and unaffected controls, and utilized these to obtain neural progenitor cells (NPCs) and differentiated neurons in vitro. These patient-derived TSC2 heterozygous NPCs were delayed in their ability to differentiate into neurons. Patient-derived progenitor cells also exhibited a modest activation of mTORC1 signaling downstream of TSC, and a marked attenuation of upstream PI3K/AKT signaling. We further show that pharmacologic AKT inhibition, but not mTORC1 inhibition, causes a neuronal differentiation delay, mimicking the patient phenotype. Together these data suggest that heterozygous TSC2 mutations disrupt neuronal development, potentially contributing to the disease neuropathology, and that this defect may result from dysregulated AKT signaling in neural progenitor cells.
2018-08-26 | GSE111584 | GEO
Project description:Tuberous Sclerosis Complex (TSC) is a disease caused by autosomal dominant mutations in the TSC1 or TSC2 genes, and is characterized by tumor susceptibility, brain lesions, seizures and behavioral impairments. The TSC1 and TSC2 genes encode proteins forming a complex (TSC), which is a major regulator and suppressor of mammalian target of rapamycin complex 1 (mTORC1), a signaling complex that promotes cell growth and proliferation. TSC1/2 loss of heterozygosity (LOH) and the subsequent complete loss of TSC regulatory activity in null cells causes mTORC1 dysregulation and TSC-associated brain lesions or other tissue tumors. However, it is not clear whether TSC1/2 heterozygous brain cells are abnormal and contribute to TSC neuropathology. To investigate this issue, we generated induced pluripotent stem cells (iPSCs) from TSC patients and unaffected controls, and utilized these to obtain neural progenitor cells (NPCs) and differentiated neurons in vitro. These patient-derived TSC2 heterozygous NPCs were delayed in their ability to differentiate into neurons. Patient-derived progenitor cells also exhibited a modest activation of mTORC1 signaling downstream of TSC, and a marked attenuation of upstream PI3K/AKT signaling. We further show that pharmacologic PI3K or AKT inhibition, but not mTORC1 inhibition, causes a neuronal differentiation delay, mimicking the patient phenotype. Together these data suggest that heterozygous TSC2 mutations disrupt neuronal development, potentially contributing to the disease neuropathology, and that this defect may result from dysregulated PI3K/AKT signaling in neural progenitor cells.
| S-EPMC6250058 | biostudies-literature
Project description:To screen genes related to the development of sweet potato tuberous roots, the high throughput sequencing of different stages of sweet potato tuberous roots was performed. The fibrous roots (FR; roots at 20 dap), developing tuberous roots (DR; roots at 60 dap) and mature tuberous roots (MR; roots at 120 dap) of Ipomoea batatas (L.) Taizhong 6 and MBP3 overexpressed lines were used for transcriptome analysis. Totally, we identified 5488 differentially expressed genes between different stage tuberous roots of Taizhong6 and 14312 differentially expressed genes between the tuberous roots of Taizhong6 and MBP3 overexpressed lines, by calculating the gene FPKM in each sample and conducting differential gene analysis. This study provides a foundation for the mechanism analysis of sweet potato tuberous root development.
2023-10-12 | GSE245185 | GEO
Project description:Cassava (Manihot esculenta) is one of the most important staple food crops worldwide. Its starchy tuberous roots supply over 800 million people with carbohydrates. Yet, surprisingly little is known about the processes involved in filling of those vital storage organs. A better understanding of cassava carbohydrate allocation and starch storage is key to improve storage root yield. In this work, we studied cassava morphology and phloem sap flow from source to sink using transgenic pAtSUC2::GFP plants, the phloem tracers esculin and 5(6)-carboxyfluorescein diacetate (CFDA), as well as several staining techniques. We show that cassava performs apoplasmic phloem loading in source leaves and symplasmic unloading into phloem parenchyma cells of tuberous roots. We demonstrate that vascular rays play an important role in radial transport from the phloem to xylem parenchyma cells in tuberous roots. Furthermore, enzymatic and proteomic measurements of storage root tissues confirmed high abundance and activity of enzymes involved in the sucrose synthase-mediated pathway and indicated that starch is stored most efficiently in the outer xylem layers of tuberous roots. Our findings represent a first basis for biotechnological approaches aimed at improved phloem loading and enhanced carbohydrate allocation and storage in order to increase tuberous root yield of cassava.
2019-07-08 | PXD014001 | Pride
Project description:Tuberous root formation is a complex process consisting of phase changes as well as cell division and elongation for radial growth. We performed an integrated analysis to clarify the relationships among metabolites, phytohormones, and gene transcription during tuberous root formation in cassava (Manihot esculenta Crantz). We also confirmed the effects of the auxin (AUX), cytokinin (CK), abscisic acid (ABA), jasmonic acid (JA), gibberellin (GA), brassinosteroid (BR), salicylic acid (SA), and indole-3-acetic acid conjugated with aspartic acid (IAAsp) on tuberous root development. An integrated analysis of metabolites and gene expression indicated the expression levels of several genes encoding enzymes involved in starch biosynthesis and sucrose metabolism are up-regulated during tuberous root development, which is consistent with the accumulation of starch, sugar phosphates, and nucleotides. An integrated analysis of phytohormones and gene transcripts revealed a relationship among AUX signaling, CK signaling, and BR signaling, with AUX, CK, and BR inducing tuberous root development. In contrast, ABA and JA inhibited tuberous root development. These phenomena might represent the differences between stem tubers (e.g., potato) and root tubers (e.g., cassava). On the basis of these results, a phytohormonal regulatory model for tuberous root development was constructed. This model may be useful for future phytohormonal studies involving cassava.
2021-12-29 | GSE143278 | GEO
Project description:Investigation of whole transcriptome gene expression level during tuberous root formation and development in sweetpotato (Ipomoea batatas) cv. Guangshu 87 Identification of transcription factors (TFs) during tuberous root formation and development in sweetpotato (Ipomoea batatas) cv. Guangshu 87 A total of 7 samples were analyzed using RNA isolated from sweetpotato roots at 10, 15, 20, 30, 60, 90, 120days after transplanting. Each sample had two biological replicates.
2015-07-12 | E-GEOD-48834 | biostudies-arrayexpress
Project description:Investigation of whole transcriptome gene expression level during tuberous root formation and development in sweetpotato (Ipomoea batatas) cv. Guangshu 87 Identification of transcription factors (TFs) during tuberous root formation and development in sweetpotato (Ipomoea batatas) cv. Guangshu 87
2015-07-12 | GSE48834 | GEO
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:In this study, we analyzed the expression profiles of both mRNAs and miRNAs in tuberous roots at an early stage before cortex splitting (ES), cortex splitting stage (CSS), and secondary root thickening stage (RTS) in turnip based on high-throughput sequencing technology.
2015-09-23 | E-MTAB-5073 | biostudies-arrayexpress
Project description:The Genomic Landscape of Tuberous Sclerosis Complex
| PRJNA383009 | ENA