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Fetal brain mTOR signaling activation in tuberous sclerosis complex
- Source :
- Cerebral cortex (New York, N.Y., 24(2), 315-327. Oxford University Press
- Publication Year :
- 2012
-
Abstract
- 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-PKCĪ± (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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 14602199 and 10473211
- Volume :
- 24
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Cerebral cortex (New York, N.Y. : 1991)
- Accession number :
- edsair.doi.dedup.....5a91e4c7bfcb7ba14cf49680ac932f20