1. Modulation of the PI 3-kinase–Akt signalling pathway by IGF-I and PTEN regulates the differentiation of neural stem/precursor cells
- Author
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Gaizka Otaegi, José L. Abad, Enrique J. de la Rosa, Eva Vergaño-Vera, Ana C. Carrera, Flora de Pablo, María J. Yusta-Boyo, Carlos Vicario-Abejón, Manuel A. González, and Héctor R. Méndez-Gómez
- Subjects
Cell death ,PTEN ,Morpholines ,medicine.medical_treatment ,PI 3-kinase–Akt ,In Vitro Techniques ,Mice ,Phosphatidylinositol 3-Kinases ,medicine ,Animals ,Insulin-Like Growth Factor I ,Protein kinase B ,Cells, Cultured ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Phosphoinositide-3 Kinase Inhibitors ,Embryonic Induction ,Mice, Knockout ,Neurons ,biology ,Stem Cells ,Growth factor ,Neurogenesis ,PTEN Phosphohydrolase ,Cell Differentiation ,Cell Biology ,Embryo, Mammalian ,Neural stem cell ,IGF-I ,Olfactory bulb ,Cell biology ,Oncogene Protein v-akt ,Chromones ,Astrocytes ,Differentiation ,biology.protein ,Mutant Proteins ,Olfactory bulb stem cells ,Stem cell ,Signal Transduction - Abstract
10 páginas, 8 figuras -- PAGS nros. 2739-2748, Neural stem cells depend on insulin-like growth factor I (IGF-I) for differentiation. We analysed how activation and inhibition of the PI 3-kinase–Akt signalling affects the number and differentiation of mouse olfactory bulb stem cells (OBSCs). Stimulation of the pathway with insulin and/or IGF-I, led to an increase in Akt phosphorylated on residues Ser473 and Thr308 (P-AktSer473 and P-AktThr308, respectively) in proliferating OBSCs, and in differentiating cells. Conversely, P-AktSer473 levels decreased by 50% in the OB of embryonic day 16.5-18.5 IGF-I knockout mouse embryos. Overexpression of PTEN, a negative regulator of the PI 3-kinase pathway, caused a reduction in the basal levels of P-AktSer473 and P-AktThr308 and a minor reduction in IGF-I-stimulated P-AktSer473. Although PTEN overexpression decreased the proportion of neurons and astrocytes in the absence of insulin/IGF-I, it did not alter the proliferation or survival of OBSCs. Accordingly, overexpression of a catalytically inactive PTEN mutant promoted OBSCs differentiation. Inhibition of PI 3-kinase by LY294002 produced strong and moderate reductions in IGF-I-stimulated P-AktSer473 and P-AktThr308, respectively. Consequently, LY294002 reduced the proliferation of OBSCs and the number of neurons and astrocytes, and also augmented cell death. These findings indicate that OBSC differentiation is more sensitive to lower basal levels of P-Akt than proliferation or death. By regulating P-Akt levels in opposite ways, IGF-I and PTEN contribute to the fine control of neurogenesis in the olfactory bulb, This work was funded by the grants from the MEC (Spain) BFU 2004-2352 to F.d.P., SAF2004-05798 to C.V.-A. and BMC 2003-07751 to E.J.d.l.R., and from the Fundación "la Caixa" NE03/72-02 to C.V.-A. G.O., M.J.Y.-B, E.V.-V. and H.R.M.-G. were supported by doctoral fellowships either from the MEC or the "Comunidad Autónoma de Madrid"
- Published
- 2006