Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany; Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
J Neurochem. 2014 Jul;130(2):255-67. doi: 10.1111/jnc.12718. Epub 2014 May 3.
Development of the cerebral cortex is controlled by growth factors among which transforming growth factor beta (TGFβ) and insulin-like growth factor 1 (IGF1) have a central role. The TGFβ- 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 TGFβ 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. TGFβ 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. Within developing cortical cells TGFβ- and IGF-signalling activities are timely separated. TGFβ dominates in E16.5-derived cells and drives neuronal differentiation. IGF influences survival, proliferation and neuronal differentiation in E13.5-derived cells. mTORC2-signalling in E16.5-derived cells influences survival, proliferation and differentiation, activated through PI3K-p110-alpha. PI3K-p110-beta-signalling activates a different mTORC2. Both PI3K/mTORC2-signalling pathways are required but not directly activated in TGFβ-mediated neuronal differentiation.
大脑皮层的发育受生长因子的控制，其中转化生长因子β（TGFβ）和胰岛素样生长因子 1（IGF1）起着核心作用。TGFβ-和 IGF1 途径相互作用并共享信号分子，但在中枢神经系统中，假定的交叉点仍不清楚。我们研究了来自 E13.5 和 E16.5 两个发育时间点的小鼠大脑皮层细胞中 TGFβ 和 IGF1 的生物学效应和下游分子。IGF1 主要在 E13.5 衍生的细胞中诱导 PI3K、AKT 和雷帕霉素哺乳动物靶标复合物（mTORC1/mTORC2），导致增殖、存活和神经元分化，但对 E16.5 衍生的细胞影响较小。TGFβ 在 E13.5 时作用较小。它不会直接激活 PI3K 和 mTOR 信号网络，但需要其活性来专门在 E16.5 时介导神经元分化。我们的数据表明 mTORC2 在 E16.5 衍生的皮层细胞的存活、增殖和神经元分化中起着核心作用。mTORC2 促进这些细胞过程，并且受 PI3K-p110-alpha 信号的控制。E16.5 衍生的细胞中，PI3K-p110-beta 信号激活 mTORC2，但不影响细胞存活、增殖和分化。这一发现表明，不同的 mTORC2 亚型可能与皮质发育有关，并且这些亚型受不同的 PI3K 同工型控制。在发育中的皮层细胞中，TGFβ-和 IGF 信号活动是及时分离的。TGFβ 在 E16.5 衍生的细胞中占主导地位，并驱动神经元分化。IGF 在 E13.5 衍生的细胞中影响存活、增殖和神经元分化。E16.5 衍生的细胞中的 mTORC2 信号影响存活、增殖和分化，通过 PI3K-p110-alpha 激活。PI3K-p110-beta 信号激活不同的 mTORC2。在 TGFβ 介导的神经元分化中，两种 PI3K/mTORC2 信号通路都需要，但不直接激活。
