Transforming Growth Factor β (TGFβ) Mediates Schwann Cell Death<i>In Vitro</i>and<i>In Vivo</i>: Examination of c-Jun Activation, Interactions with Survival Signals, and the Relationship of TGFβ-Mediated Death to Schwann Cell Differentiation

Abstract

In some situations, cell death in the nervous system is controlled by an interplay between survival factors and negative survival signals that actively induce apoptosis. The present work indicates that the survival of Schwann cells is regulated by such a dual mechanism involving the negative survival signal transforming growth factor β (TGFβ), a family of growth factors that is present in the Schwann cells themselves. We analyze the interactions between this putative autocrine death signal and previously defined paracrine and autocrine survival signals and show that expression of a dominant negative c-Jun inhibits TGFβ-induced apoptosis. This and other findings pinpoint activation of c-Jun as a key downstream event in TGFβ-induced Schwann cell death. The ability of TGFβ to kill Schwann cells, like normal Schwann cell death <i>in vivo</i>, is under a strong developmental regulation, and we show that the decreasing ability of TGFβ to kill older cells is attributable to a decreasing ability of TGFβ to phosphorylate c-Jun in more differentiated cells.