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The Journal of Neuroscience, June 15, 1999, 19(12):4828-4838
Nerve Growth Factor Signaling through p75 Induces Apoptosis in Schwann Cells via a Bcl-2-Independent Pathway
Merja Soilu-Hänninen1, Paul Ekert1, Tamara Bucci1, Daniel Syroid2, Perry F. Bartlett1, and Trevor J. Kilpatrick1 1 The Walter and Eliza Hall Institute of Medical Research, The Royal Melbourne Hospital, Parkville Victoria 3050, Australia, and 2 The Salk Institute for Biological Studies, La Jolla, California 92186-5800
Apoptosis is involved in the regulation of Schwann cell numbers during normal development and after axonal damage, but the molecular regulation of Schwann cell death remains unknown. We have used stably transfected rat Schwann 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 apoptosis induced by survival factor withdrawal, whereas CrmA did not. In contrast, Bcl-2-transfected Schwann cells were susceptible to apoptosis in response to exogenous NGF, whereas CrmA-expressing cell lines were resistant. Demonstration of high levels of the low-affinity neurotrophin receptor p75 but not the high-affinity TrkA receptor on the Bcl-2-transfected cell lines suggested that the NGF-induced killing was mediated by p75. This was confirmed 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-type 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 conditions that promoted survival but was downregulated to undetectable levels after survival factor withdrawal. In conclusion, our results demonstrate the existence of two separate pathways that expedite apoptosis in Schwann cells: a Bcl-2-blockable pathway initiated on loss of trophic support, and a Bcl-2-independent, CrmA-blockable pathway mediated via the p75 receptor.
Key words: apoptosis; neurotrophins; Schwann cells; nerve growth factor; Bcl-2; low-affinity neurotrophin receptor
Copyright © 1999 Society for Neuroscience 0270-6474/99/19124828-11$05.00/0
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