Fetal brain mTOR signaling activation in tuberous sclerosis complex
| Autor: | Jacqueline Estevez, Ksenia A. Orlova, Eleonora Aronica, Jacqueline F. Birnbaum, Whitney E. Parker, Harvey B. Sarnat, Victoria Tsai, Marianna Baybis, Laura Flores-Sarnat, Peter B. Crino, Anthony W. S. Chi, Benjamin D. Berg, Kei Okochi |
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| Přispěvatelé: | ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Neurology, Pathology |
| Rok vydání: | 2012 |
| Předmět: |
Adult
Male congenital hereditary and neonatal diseases and abnormalities Cognitive Neuroscience mTORC1 Mechanistic Target of Rapamycin Complex 2 Biology Mechanistic Target of Rapamycin Complex 1 mTORC2 Cellular and Molecular Neuroscience Mice Neural Stem Cells Cell Movement Tuberous Sclerosis Complex 2 Protein medicine Animals Humans Enzyme Inhibitors PI3K/AKT/mTOR pathway Cells Cultured Myelin Sheath Cell Size Sirolimus TOR Serine-Threonine Kinases Tumor Suppressor Proteins Brain Articles Molecular biology Neural stem cell Cell biology Mice Inbred C57BL Multiprotein Complexes Signal transduction TSC2 Stem cell biological phenomena cell phenomena and immunity medicine.drug Signal Transduction |
| Zdroj: | Cerebral cortex (New York, N.Y., 24(2), 315-327. Oxford University Press |
| ISSN: | 1460-2199 1047-3211 |
| Popis: | Tuberous sclerosis complex (TSC) is characterized by developmental malformations of the cerebral cortex known as tubers, comprised of cells that exhibit enhanced mammalian target of rapamycin (mTOR) signaling. To date, there are no reports of mTORC1 and mTORC2 activation in fetal tubers or in neural progenitor cells lacking Tsc2. We demonstrate mTORC1 activation by immunohistochemical detection of substrates phospho-p70S6K1 (T389) and phospho-S6 (S235/236), and mTORC2 activation by substrates phospho-PKCα (S657), phospho-Akt (Ser473), and phospho-SGK1 (S422) in fetal tubers. Then, we show that Tsc2 shRNA knockdown (KD) in mouse neural progenitor cells (mNPCs) in vitro results in enhanced mTORC1 (phospho-S6, phospho-4E-BP1) and mTORC2 (phospho-Akt and phospho-NDRG1) signaling, as well as a doubling of cell size that is rescued by rapamycin, an mTORC1 inhibitor. Tsc2 KD in vivo in the fetal mouse brain by in utero electroporation causes disorganized cortical lamination and increased cell volume that is prevented with rapamycin. We demonstrate for the first time that mTORC1 and mTORC2 signaling is activated in fetal tubers and in mNPCs following Tsc2 KD. These results suggest that inhibition of mTOR pathway signaling during embryogenesis could prevent abnormal brain development in TSC. |
| Databáze: | OpenAIRE |
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