Akt-Mediated Survival of Oligodendrocytes Induced by Neuregulins

Abstract

Neuregulins have been implicated in a number of events in cells in the oligodendrocyte lineage, including enhanced survival, mitosis, migration, and differentiation. At least two signaling pathways have been shown to be involved in neuregulin signaling: the phosphatidylinositol (PI)-3 kinase and the mitogen-activated protein kinase pathways. In the present studies, we examined the signaling pathway involved in the survival function of heregulin, focusing on heregulin-induced changes in Akt activity in cultured glial cells, and the consequences of Akt activation in cells in the oligodendrocyte lineage. Heregulin binds erbB receptors, and in our studies, primary cultures of both oligodendrocyte progenitor cells and differentiating oligodendrocytes expressed erbB2, erbB3, and erbB4 receptors. In C6 glioma cells and primary cultures of oligodendrocytes, heregulin induced time-and dosedependent Akt phosphorylation at Ser 473 in a wortmanninsensitive manner. To investigate further the signaling pathway for heregulin in glial cells, BAD was overexpressed in C6 glioma cells. In these cells, heregulin induced phosphorylation of BAD at Ser 136 . Apoptosis of oligodendrocyte progenitor cells induced by growth factor deprivation was effectively blocked by heregulin in a wortmannin-sensitive manner. Overexpression of dominant negative Akt but not of wild-type Akt by adenoviral gene transfer in primary cultures of both oligodendrocytes and their progenitors induced significant apoptosis through activation of the caspase cascade. The present data suggest that the survival function of heregulin is mediated through the PI-3 kinase/Akt pathway in cells in the oligodendrocyte lineage and that the Akt pathway may be quite important for survival of cells in this lineage.

Edg8/S1P5: An Oligodendroglial Receptor with Dual Function on Process Retraction and Cell Survival

“…In this respect, our results are in agreement with previously identified roles of S1P in Akt activation and survival of hepatic myofibroblast or endothelial cells (Morales-Ruiz et al, 2001;Davaille et al, 2002). A variety of different agents have been shown to promote oligodendrocyte survival, and some such as NT3, IGF-I, and neuregulin (Vemuri and McMorris, 1996;Flores et al, 2000) signal through the phosphatidylinositol 3Ј-kinase (PI3K) transduction pathway. S1P therefore appears to be another oligodendroglial survival factor, signaling through the Akt pathway downstream of the Edg8/S1P5 receptor.…”

“…9A). Because the Akt signaling cascade has been previously shown to be involved in oligodendrocyte survival (Vemuri and McMorris, 1996;Flores et al, 2000), we performed an immunoblot with an anti-phosphoAkt mAb on S1P-treated cell extracts from mature oligodendrocytes. Exposure of mature oligodendrocytes to S1P for 15 min induced a robust phosphorylation of Akt, which was mainly prevented by incubation of the cells with PTX (Fig.…”

“…These developmental stages, which are associated with different capacities of proliferation, migration, differentiation, survival, maturation, and finally myelin deposition, are cell autonomous but also depend on a variety of extrinsic factors. Growth factors (PDGF-A, FGF-2, IGF-I, CNTF, neuregulins, and neurotrophins) have been shown to affect proliferation, survival, and differentiation of oligodendrocyte precursor cells (OPCs) (Barres et al, 1992;Bansal and Pfeiffer, 1997;Flores et al, 2000;Sim et al, 2002). Guidance molecules, such as semaphorins 3A, 3F, and netrin-1, guide the migration of OPCs during development (Sugimoto et al, 2001;Spassky et al, 2002;Tsai and Miller, 2002;Jarjour et al, 2003).…”

Apoptotic Cell Death Following Traumatic Injury to the Central Nervous System

“…Akt (also known as protein kinase B) is a serine/threonine protein kinase that transduces intracellular anti-apoptotic signals that are mediated by serum or growth factors that activate phosphoinositide 3-kinase, or PI3-kinase (Franke et al, 1995;Datta et al, 1997;Dudek et al, 1997;Kennedy et al, 1997;Coffer et al, 1998;Downward 1998;Nunez and del Peso, 1998;Goswami et al, 1999;Kennedy et al, 1999;Flores et al, 2000). Overexpression of Akt prevents apoptosis in certain cells, including neurons, following withdrawal of serum or growth factors (Yao and Cooper, 1995;Datta et al, 1997;Dudek et al, 1997;Crowder and Freeman, 1998;Eves et al, 1998;Ulrich et al, 1998;Bhave et al, 1999;Vaillant et al, 1999;Virdee et al, 1999;Flores et al, 2000;Kermer et al, 2000). The precise mechanisms by which Akt promotes cell survival are not entirely clear.…”

Dysfunction of Platelet-derived Growth Factor Receptor α (PDGFRα) Represses the Production of Oligodendrocytes from Arylsulfatase A-deficient Multipotential Neural Precursor Cells

“…This most likely stems from lowered association of the receptor with DRMs in ASA Ϫ/Ϫ NPs. Interestingly, the survival/expansion of OPC mediated by PDGF-AA involves the activation of AKT through phosphorylation of residues Thr 308 and Ser 473 (68,69). Our results demonstrate that in the presence of high levels of sulfatides, the relocalization of PDGFR␣ to non-DRM domains and phosphorylation of Thr 308 and Ser 473 of AKT are severely compromised.…”