Transforming growth factor beta (TGF beta) mediates schwann cell death in vitro and in vivo: Examination of c-jun activation, interactions with survival signals, and the relationship of TGF beta-mediated death to schwann cell differentiation

In some situations, cell death in the nervous system is controlled by an in terplay between survival factors and negative survival signals that activel y induce apoptosis. The present work indicates that the survival of Schwann cells is regulated by such a dual mechanism involving the negative surviva l signal transforming growth factor beta (TGF beta), a family of growth fac tors that is present in the Schwann cells themselves. We analyze the intera ctions between this putative autocrine death signal and previously defined paracrine and autocrine survival signals and show that expression of a domi nant negative c-Jun inhibits TGF beta -induced apoptosis. This and other fi ndings pinpoint activation of c-Jun as a key downstream event in TGF beta - induced Schwann cell death. The ability of TGF beta to kill Schwann cells, like normal Schwann cell death in vivo, is under a strong developmental reg ulation, and we show that the decreasing ability of TGF beta to kill older cells is attributable to a decreasing ability of TGF beta to phosphorylate c-Jun in more differentiated cells.