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© The Rockefeller University Press, 0021-9525/1998//911 $5.00
The Journal of Cell Biology, Volume 140, Number 4, , 1998 911-923

Article

The p75 Neurotrophin Receptor Mediates Neuronal Apoptosis and Is Essential for Naturally Occurring Sympathetic Neuron Death



Shernaz X. Bamji, Marta Majdan, Christine D. Pozniak, Daniel J. Belliveau, Raquel Aloyz, Judi Kohn, Carrie G. Causing, and Freda D. Miller

Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4

Abstract. To determine whether the p75 neurotrophin receptor (p75NTR) plays a role in naturally occurring neuronal death, we examined neonatal sympathetic neurons that express both the TrkA tyrosine kinase receptor and p75NTR. When sympathetic neuron survival is maintained with low quantities of NGF or KCl, the neurotrophin brain-derived neurotrophic factor (BDNF), which does not activate Trk receptors on sympathetic neurons, causes neuronal apoptosis and increased phosphorylation of c-jun. Function-blocking antibody studies indicate that this apoptosis is due to BDNF-mediated activation of p75NTR. To determine the physiological relevance of these culture findings, we examined sympathetic neurons in BDNF–/– and p75NTR–/– mice. In BDNF–/– mice, sympathetic neuron number is increased relative to BDNF+/+ littermates, and in p75NTR–/– mice, the normal period of sympathetic neuron death does not occur, with neuronal attrition occurring later in life. This deficit in apoptosis is intrinsic to sympathetic neurons, since cultured p75NTR–/– neurons die more slowly than do their wild-type counterparts. Together, these data indicate that p75NTR can signal to mediate apoptosis, and that this mechanism is essential for naturally occurring sympathetic neuron death.

We thank O.-M. Nicolesu (McGill University, Montreal, Canada) for her help with some of these experiments; A. Speelman and R. Varma (both of McGill University) for excellent technical assistance; and D. Kaplan and members of the Miller laboratory for their advice and input throughout the course of this work.

This study was supported by grants from the Canadian Medical Research Council and NeuroSciences Network (to F.D. Miller). During the course of this work, D.J. Belliveau was a Medical Research Council (MRC)/Genentech fellow, R. Aloyz a NeuroSciences Network fellow, and F.D. Miller a Killam Scholar. S.X. Bamji and C.D. Pozniak are funded by MRC studentships, and J. Kohn and C. Causing were supported by studentships from Fonds pour la Formation de Chercheurs et l'Aide à la Recherche and the Savoy Foundation, respectively.

S.X. Bamji and M. Majdan contributed equally to this work.

Address all correspondence to F.D. Miller, Center for Neuronal Survival, Montreal Neurological Institute, McGill University, 3801 rue University, Montreal, Quebec, Canada H3A 2B4. Tel.: (514) 398-4261. Fax: (514) 398-1319. E-mail: mdfm{at}musica.mcgill.ca

D.J. Belliveau's present address is Department of Anatomy and Cell Biology, University of Western Ontario, London, Canada M6A SC1.

1. Abbreviations used in this paper: BDNF, brain-derived neurotrophic factor; JNK, jun kinase; NT-3 and NT-4, neurotrophin-3 and neurotrophin-4; NTR, neurotrophin receptor; p75NTR, p75 neurotrophin receptor; SCG, superior cervical ganglion.


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