Modulation of the PI 3-kinase–Akt signalling pathway by IGF-I and PTEN regulates the differentiation of neural stem/precursor cells

Abstract

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.

Activation of tumor suppressor protein PTEN and induction of apoptosis are involved in cAMP-mediated inhibition of cell number in B92 glial cells

“…Many reports have suggested that PTEN plays a critical role in brain development and cell phenotype changes [7,14,15]. In order to further investigate the role of PTEN in cAMP-regulated cell growth, we performed western blotting analyses using the phospho-specific antibodies, phospho-PTEN (Ser380) antibody and phospho-Akt (Ser473) antibody.…”

Inflammation, plasticity and real-time imaging after cerebral ischemia

“…Namely, changing the state of microglial activation from highly-activated to proliferating was associated with the signiWcant decrease in TNF-production and the increase in IGF-1 secretion [79]. IGF-1 is a known anti-apoptotic factor and recent reports suggest that it plays an important role in promotion of proliferation and diVerentiation of neuronal progenitors [65,107,145]. Contrary to IGF-1, the studies performed on the transgenic animals lacking TNFR1 revealed that TNFR1 acts as a negative regulator of neuronal progenitors in hippocampus and in SVZ area after stroke [59,60].…”

Growth factors, stem cells, and stroke

“…A majority of growth factors bind to their receptors and activate downstream signaling pathways to induce the expression of specific genes responsible for proliferation, differentiation, and/or migration of cells. For example, receptor-mediated activation of mitogen-activated protein kinase promotes the proliferation, 33 whereas stimulation of the phosphoinositide-dependent kinase/Akt pathway enhances the differentiation 30 of the neural stem cells. Nevertheless, some growth factors like TGF␤ and BMP-4 13 can promote the differentiation of neural stem cells by activating proteins (such as Smads), which are translocated into the nucleus to induce gene expression.…”