PI3K‐p110‐alpha‐subtype signalling mediates survival, proliferation and neurogenesis of cortical progenitor cells via activation of mTORC2

Abstract

Development of the cerebral cortex is controlled by growth factors among which transforming growth factor beta (TGFb) and insulin-like growth factor 1 (IGF1) have a central role. The TGFb-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 TGFb 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. TGFb 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

PI3K–mTORC2 but not PI3K–mTORC1 Regulates Transcription of HIF2A/EPAS1 and Vascularization in Neuroblastoma

“…Little is known about upstream and downstream effects of mTORC2, but it has been suggested to be directly or indirectly activated by PI3K (42)(43)(44)(45)(46). VHL-deficient RCC cells that constitutively express HIF2a have been shown to have differential dependency on mTORC1 and mTORC2 for HIF1a and HIF2a protein expression (20).…”

The FOXG1/FOXO/SMAD network balances proliferation and differentiation of cortical progenitors and activatesKcnh3expression in mature neurons

“…Firstly, FOXG1 and FOXO proteins might be a node of intersection between TGFβ- and IGF-signaling pathways. In contrast to this view, we recently reported that IGF1-signaling activates cell proliferation in early cortical development (E13.5), whereas TGFβ-signaling is mainly active at later stages (E16.5) [2]. Hence, FOXG1 and FOXO proteins might be cofactors that are implicated in different developmental responses to IGF1- and TGFβ-signals rather than nodes of intersection.…”

“…Since proliferation and differentiation take place simultaneously in developing organ systems, cellular interpretation of such signals has to occur cell autonomously, for example through activity of specific transcription factors. Transforming growth factor β (TGFβ) is an extrinsic cue implicated in neuronal differentiation of cortical progenitor cells (CPCs) [1, 2]. It has 3 different isoforms (TGFB1, 2, and 3) and is a member of the TGFβ superfamily, including Bone morphogenetic proteins (BMPs) and Activins.…”

PI3Kγ deficiency enhances seizures severity and associated outcomes in a mouse model of convulsions induced by intrahippocampal injection of pilocarpine

“…It has been shown that PI3K/Akt signaling regulates proliferation and inhibits differentiation of adult neural progenitors (Peltier et al, 2007). Inhibition of PI3K-p110α also interferes with cell proliferation, survival and neuronal differentiation through mTORC2 activation (Wahane et al, 2014). Besides the possible role of PI3Kγ in neurogenesis, the reduced number of DCX + cells in PI3Kγ −/− mice could also reflect the increased death of these cells.…”