ArticleProceedings of the National Academy of Sciences of the United States of America2011
Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 108 papers, 1 of them a synthesis that pooled it.
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Who cites it
108 citing papers in PubMed, 1 synthesis or guideline pooled it, 178 citations in OpenAlex.
- Genotype-phenotype correlations in focal malformations of cortical development: a pathway to integrated pathological diagnosis in epilepsy surgery.Brain pathology (Zurich, Switzerland) · 2019Pooled it
- ENT1 inhibitor J4 restores cognitive function and white-matter integrity in a mouse model of tuberous sclerosis complex.Journal of biomedical science · 2026Article
- Article
- Seizure occurrence in FCD type II is predicted by lesion position and linked to cytoarchitectural alterations.Acta neuropathologica communications · 2025Article
- High-throughput bioprinting to produce micropatterned neuroepithelial tissues and model TSC2-deficient brain malformations.Cell reports methods · 2025Article
- Spatially Organized IGF1-mTOR Signaling Controls Human Forebrain Progenitor F ate Through Coordinated Transcriptional and Translational Programs.bioRxiv : the preprint server for biology · 2025Article
- AAV hamartin gene therapy in a stochastic, cerebral mouse model of tuberous sclerosis type 1.Molecular therapy. Methods & clinical development · 2025Article
- Unraveling the function of TSC1-TSC2 complex: implications for stem cell fate.Stem cell research & therapy · 2025Review
- Developmental mechanisms underlying pediatric epilepsy.Frontiers in neurology · 2025Review
- Involvement of Autophagic Machinery in Neuropathogenesis: Targeting and Relevant Methods of Detection.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Cytoplasmic vacuolization and ectopic formation of perineuronal nets are characteristic pathologies of cytomegalic neurons in tuberous sclerosis.Journal of neuropathology and experimental neurology · 2024Article
- The molecular genetics of PI3K/PTEN/AKT/mTOR pathway in the malformations of cortical development.Genes & diseases · 2024Review
- Seizures exacerbate excitatory: inhibitory imbalance in Alzheimer's disease and 5XFAD mice.Brain : a journal of neurology · 2024Article
- Rodent Models for ASD Biomarker Development.Advances in neurobiology · 2024Review
- Isolated subependymal giant cell astrocytoma (SEGA) in the absence of clinical tuberous sclerosis: two case reports and literature review.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2024Review
- Article
- Epilepsy Severity Is Associated With Head Circumference and Growth Rate in Infants With Tuberous Sclerosis Complex.Pediatric neurology · 2023Observational
- Specific Features of Focal Cortical Dysplasia in Tuberous Sclerosis Complex.Current issues in molecular biology · 2023Review
- Modeling genetic mosaicism of the mammalian target of rapamycin pathway in the cerebral cortex.Frontiers in mammal science · 2023Article
- Treatment-Resistant Epilepsy and Tuberous Sclerosis Complex: Treatment, Maintenance, and Future Directions.Neuropsychiatric disease and treatment · 2023Review
48 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 5 institutions in 2 countries.
Funding
Abstract
Tuberous sclerosis complex (TSC) is a multiorgan genetic disease in which brain involvement causes epilepsy, intellectual disability, and autism. The hallmark pathological finding in TSC is the cerebral cortical tuber and its unique constituent, giant cells. However, an animal model that replicates giant cells has not yet been described. Here, we report that mosaic induction of Tsc1 loss in neural progenitor cells in Tsc1(cc) Nestin-rtTA(+) TetOp-cre(+) embryos by doxycycline leads to multiple neurological symptoms, including severe epilepsy and premature death. Strikingly, Tsc1-null neural progenitor cells develop into highly enlarged giant cells with enlarged vacuoles. We found that the vacuolated giant cells had multiple signs of organelle dysfunction, including markedly increased mitochondria, aberrant lysosomes, and elevated cellular stress. We found similar vacuolated giant cells in human tuber specimens. Postnatal rapamycin treatment completely reversed these phenotypes and rescued the mutants from epilepsy and premature death, despite prenatal onset of Tsc1 loss and mTOR complex 1 activation in the developing brain. This TSC brain model provides insights into the pathogenesis and organelle dysfunction of giant cells, as well as epilepsy control in patients with TSC.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.