Journal
JOURNAL OF NEUROCHEMISTRY
Volume 130, Issue 2, Pages 255-267Publisher
WILEY
DOI: 10.1111/jnc.12718
Keywords
brain; cerebral cortex; insulin; neuron; PI3K-isoform; PI3K-subunit
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Funding
- EC [LSHG-CT-2007-036894]
- Schlieben-Lange-Programm
- BMBF GerontoSys II - NephAge [031 5896A]
- University of Groningen, NL
- Stiftung der Deutschen Wirtschaft
- German Research Foundation DFG
- Excellence Initiative of the German Research Foundation [EXC 294]
- Excellence Initiative of the German Research Foundation (Spemann Graduate School) [GSC-4]
- Freiburg institute for Advanced Studies FRIAS Junior Fellowship
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Development of the cerebral cortex is controlled by growth factors among which transforming growth factor beta (TGF beta) and insulin-like growth factor 1 (IGF1) have a central role. The TGF beta- and IGF1-pathways cross-talk and share signalling molecules, but in the central nervous system putative points of intersection remain unknown. We studied the biological effects and down-stream molecules of TGF beta and IGF1 in cells derived from the mouse cerebral cortex at two developmental time points, E13.5 and E16.5. IGF1 induces PI3K, AKT and the mammalian target of rapamycin complexes (mTORC1/mTORC2) primarily in E13.5-derived cells, resulting in proliferation, survival and neuronal differentiation, but has small impact on E16.5-derived cells. TGF beta has little effect at E13.5. It does not activate the PI3K- and mTOR-signalling network directly, but requires its activity to mediate neuronal differentiation specifically at E16.5. Our data indicate a central role of mTORC2 in survival, proliferation as well as neuronal differentiation of E16.5-derived cortical cells. mTORC2 promotes these cellular processes and is under control of PI3K-p110-alpha signalling. PI3K-p110-beta signalling activates mTORC2 in E16.5-derived cells but it does not influence cell survival, proliferation and differentiation. This finding indicates that different mTORC2 subtypes may be implicated in cortical development and that these subtypes are under control of different PI3K isoforms
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