Modulation of the PI 3-kinase-Akt signalling pathway by IGF-I and PTEN regulates the differentiation of neural stem/precursor cells.
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.
Otaegi
Gaizka
G
Group of Growth Factors in Vertebrate Development, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Ramiro de Maeztu 9, Madrid 28040, Spain.
Yusta-Boyo
María J
MJ
Vergaño-Vera
Eva
E
Méndez-Gómez
Héctor R
HR
Carrera
Ana C
AC
Abad
José L
JL
González
Manuel
M
de la Rosa
Enrique J
EJ
Vicario-Abejón
Carlos
C
de Pablo
Flora
F
D000818:Animals; D001253:Astrocytes / Q000502:physiology; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004622:Embryo, Mammalian; D004627:Embryonic Induction; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D050505:Mutant Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction; D013234:Stem Cells / Q000502:physiology*
D002867:Chromones; D007334:Insulin-Like Growth Factor I; D009025:Morpholines; D050505:Mutant Proteins; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C487757:Pten protein, mouse