Nerve growth factor signaling through p75 induces apoptosis in Schwann cells via a Bcl-2-independent pathway

Apoptosis is involved in the regulation of Schwann cell numbers during norm al development and after axonal damage, but the molecular regulation of Sch wann cell death remains unknown. We have used stably transfected rat Schwan n cell lines to study the potential roles of nerve growth factor (NGF), the antiapoptotic protein Bcl-2 and the cytokine response modifier A (CrmA) in modulating Schwann cell death in vitro. Bcl-2 inhibited Schwann cell apopt osis induced by survival factor withdrawal, whereas CrmA did not. In contra st, Bcl-2-transfected Schwann cells were susceptible to apoptosis in respon se to exogenous NGF, whereas CrmA-expressing cell lines were resistant. Dem onstration of high levels of the low-affinity neurotrophin receptor p75 but not the high-affinity TrkA receptor on the Bcl-2-transfected cell lines su ggested that the NGF-induced killing was mediated by p75. This was confirme d by resistance of Schwann cells isolated from p75 knockout mice to the NGF -induced cell death. Nerve growth factor also promoted the death of wild-ty pe mouse and rat Schwann cells in the absence of survival factor withdrawal . Endogenous Bcl-2 mRNA was expressed by wild-type Schwann cells in all con ditions that promoted survival but was downregulated to undetectable levels after survival factor withdrawal. In conclusion, our results demonstrate t he existence of two separate pathways that expedite apoptosis in Schwann ce lls: a Bcl-2-blockable pathway initiated on loss of trophic support, and a Bcl-2-independent, CrmA-blockable pathway mediated via the p75 receptor.