The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex
Open accessAbstract
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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Cites
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Self-citationBiallelic TSC gene inactivation in tuberous sclerosis complex
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Cited by
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TSC1 controls macrophage polarization to prevent inflammatory disease
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Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex
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Self-citationMitochondrial abnormalities in temporal lobe of autistic brain
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Amplification of human interneuron progenitors promotes brain tumors and neurological defects
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Metadata
- Authors
- Goto, J., Talos, D. M., Klein, P., Qin, W., Chekaluk, Y. I., Anderl, S., Malinowska, I. A., Di Nardo, A., Bronson, R. T., Chan, J. A., Vinters, H. V., Kernie, S. G., Jensen, F. E., Sahin, M., & Kwiatkowski, D. J.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2011-10-24
- Volume
- 108
- Issue
- 45
- Pages
- E1070-9
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2020209656
- Cited by
- 179
- References
- 10
- FWCI
- 12.71
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Goto, J., Talos, D. M., Klein, P., Qin, W., Chekaluk, Y. I., Anderl, S., Malinowska, I. A., Di Nardo, A., Bronson, R. T., Chan, J. A., Vinters, H. V., Kernie, S. G., Jensen, F. E., Sahin, M., & Kwiatkowski, D. J. (2011). Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1106454108
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
