Akt-mediated survival of oligodendrocytes induced by neuregulins

Neuregulins have been implicated in a number of events in cells in the olig odendrocyte lineage, including enhanced survival, mitosis, migration, and d ifferentiation. At least two signaling pathways have been shown to be invol ved in neuregulin signaling: the phosphatidylinositol (PI)-3 kinase and the mitogen-activated protein kinase pathways. In the present studies, we exam ined the signaling pathway involved in the survival function of heregulin, focusing on heregulin-induced changes in Akt activity in cultured glial cel ls, and the consequences of Akt activation in cells in the oligodendrocyte lineage. Heregulin binds erbB receptors, and in our studies, primary cultur es of both oligodendrocyte progenitor cells and differentiating oligodendro cytes expressed erbB2, erbB3, and erbB4 receptors. In C6 glioma cells and p rimary cultures of oligodendrocytes, heregulin induced time- and dose-depen dent Akt phosphorylation at Ser(473) in a wortmannin-sensitive manner. To i nvestigate further the signaling pathway for heregulin in glial cells, BAD was overexpressed in C6 glioma cells. In these cells, heregulin induced pho sphorylation of BAD at Ser(136). Apoptosis of oligodendrocyte progenitor ce lls induced by growth factor deprivation was effectively blocked by heregul in in a wortmannin-sensitive manner. Overexpression of dominant negative Ak t but not of wild-type Akt by adenoviral gene transfer in primary cultures of both oligodendrocytes and their progenitors induced significant apoptosi s 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 m ay be quite important for survival of cells in this lineage.