ArticleMolecular and cellular neurosciences2018
Neural progenitors derived from Tuberous Sclerosis Complex patients exhibit attenuated PI3K/AKT signaling and delayed neuronal differentiation.
Article in Molecular and cellular neurosciences, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 52 citations in OpenAlex.
- Spatially Organized IGF1-mTOR Signaling Controls Human Forebrain Progenitor F ate Through Coordinated Transcriptional and Translational Programs.bioRxiv : the preprint server for biology · 2025Article
- Creatine mitigates neurogenesis impairment caused by defective DcpS decapping.Scientific reports · 2025Article
- The enhancer module of Integrator controls cell identity and early neural fate commitment.Nature cell biology · 2025Article
- In and out: Benchmarking in vitro, in vivo, ex vivo, and xenografting approaches for an integrative brain disease modeling pipeline.Stem cell reports · 2024Review
- Modeling tuberous sclerosis complex with human induced pluripotent stem cells.World journal of pediatrics : WJP · 2024Review
- Article
- Translatome analysis of tuberous sclerosis complex 1 patient-derived neural progenitor cells reveals rapamycin-dependent and independent alterations.Molecular autism · 2023Article
- Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis.Biology open · 2023Article
- Review
- Signalling pathways in autism spectrum disorder: mechanisms and therapeutic implications.Signal transduction and targeted therapy · 2022Review
- mRNA-Decapping Associated DcpS Enzyme Controls Critical Steps of Neuronal Development.Cerebral cortex (New York, N.Y. : 1991) · 2022Article
- Hyperactivation of mTORC1 in a double hit mutant zebrafish model of tuberous sclerosis complex causes increased seizure susceptibility and neurodevelopmental abnormalities.Frontiers in cell and developmental biology · 2022Article
- Lineage recording in human cerebral organoids.Nature methods · 2022Article
- Research models of neurodevelopmental disorders: The right model in the right place.Frontiers in neuroscience · 2022Review
- PI3K/mTOR inhibitor omipalisib prolongs cardiac repolarization along with a mild proarrhythmic outcome in the AV block dog model.Frontiers in cardiovascular medicine · 2022Article
- Mechanistic target of rapamycin signaling in human nervous system development and disease.Frontiers in molecular neuroscience · 2022Review
- Review
- Recent advances in gene therapy for neurodevelopmental disorders with epilepsy.Journal of neurochemistry · 2021Review
- Patient-Derived Induced Pluripotent Stem Cells (iPSCs) and Cerebral Organoids for Drug Screening and Development in Autism Spectrum Disorder: Opportunities and Challenges.Pharmaceutics · 2021Review
- Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
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.
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