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Modulation of the PI 3-kinase–Akt signalling pathway by IGF-I and PTEN regulates the differentiation of neural stem/precursor cells
- Source :
- Digital.CSIC. Repositorio Institucional del CSIC, instname
- Publication Year :
- 2006
- Publisher :
- The Company of Biologists, 2006.
-
Abstract
- 10 páginas, 8 figuras -- PAGS nros. 2739-2748<br />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<br />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"
- 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
Subjects
Details
- ISSN :
- 14779137 and 00219533
- Volume :
- 119
- Database :
- OpenAIRE
- Journal :
- Journal of Cell Science
- Accession number :
- edsair.doi.dedup.....f16c9fb2935db0b7ec5bfe3485524144