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First published online June 20, 2006
doi: 10.1242/10.1242/jcs.03012

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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

Gaizka Otaegi¹, María J. Yusta-Boyo¹, Eva Vergaño-Vera^1,2, Héctor R. Méndez-Gómez², Ana C. Carrera³, José L. Abad⁴, Manuel González⁴, Enrique J. de la Rosa¹, Carlos Vicario-Abejón^1,2,*, and Flora de Pablo^1,*,

¹ Group of Growth Factors in Vertebrate Development, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Ramiro de Maeztu 9, Madrid 28040, Spain
² Instituto Cajal, CSIC, Avenue Dr. Arce 37, Madrid 28002, Spain
³ Centro Nacional de Biotecnología, CSIC, Universidad Autónoma, Cantoblanco, Madrid 28049, Spain
⁴ Genetrix S.L., Marconi 1, Tres Cantos, Madrid 28760, Spain

Authors for correspondence (e-mail: cvicario{at}cajal.csic.es; fdepablo{at}cib.csic.es)

Accepted 6 April 2006

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-Akt^Ser473 and P-Akt^Thr308, respectively) in proliferating OBSCs, and in differentiating cells. Conversely, P-Akt^Ser473 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-Akt^Ser473 and P-Akt^Thr308 and a minor reduction in IGF-I-stimulated P-Akt^Ser473. 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-Akt^Ser473 and P-Akt^Thr308, 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.

Key words: Olfactory bulb stem cells, IGF-I, PI 3-kinase–Akt, PTEN, Differentiation, Cell death

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