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The Journal of Neuroscience, November 17, 2004, 24(46):10521-10529; doi:10.1523/JNEUROSCI.1390-04.2004

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Cellular/Molecular
Neurotrophin Signaling through the p75 Receptor Is Deficient in traf6-/- Mice

E. Carden Yeiser,¹ Nancy J. Rutkoski,¹ Asuka Naito,² Jun-ichiro Inoue,² and Bruce D. Carter¹

¹Department of Biochemistry and Center for Molecular Neuroscience, Vanderbilt University Medical School, Nashville, Tennessee 37232, and ²Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

Activation of the neurotrophin receptor p75 has been shown to elicit opposing cellular signals. Depending on the context of the cell, p75 will either promote survival or induce apoptosis after neurotrophin stimulation. p75-induced apoptosis occurs through activation of c-Jun N-terminal kinase (JNK), whereas the survival signal is mediated by nuclear factor B (NFB). The receptor proximal signals that produce these responses are unknown, although several molecules have been identified that associate with the intracellular domain of p75. One such interactor, TRAF6, a member of the tumor necrosis factor receptor-associated factor family, has been implicated in p75 signaling. To assess the role of TRAF6 in p75 signaling, we analyzed mice with this gene deleted. In Schwann cells isolated from traf6+/+ animals, NGF elicited an 80% increase in transcription of an NFB reporter; however, in traf6-/- cells, the NGF response was abrogated. Similarly, NGF activation of JNK was not apparent in Schwann cells from mice lacking traf6. Deficiencies in p75 signaling in traf6-/- animals resulted in a loss of p75-mediated apoptosis. In sympathetic neurons cultured from traf6+/+ superior cervical ganglia (SCGs), there was an increase in JNK activation and apoptosis after BDNF binding to p75; however, traf6-/- neurons did not respond. In vivo during naturally occurring cell death, there was a 55.6% reduction in TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling)-positive cells in the SCG of postnatal day 4 traf6-/- animals relative to traf6+/+ littermates. These results indicate that TRAF6 plays an essential role in mediating p75 signal transduction and induction of apoptosis.

Key words: NGF; BDNF; TNF; neuron; apoptosis; NFB

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Received Nov 25, 2003; revised October 6, 2004; accepted October 14, 2004.

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