The mechanisms that regulate the pruning of mammalian axons are just now being elucidated. Here, we describe a mechanism by which, during developmental sympathetic axon competition, winning axons secrete brain-derived neurotrophic factor (BDNF) in an activity-dependent fashion, which binds to the p75 neurotrophin receptor (p75NTR) on losing axons to cause their degeneration and, ultimately, axon pruning. Specifically, we found that pruning of rat and mouse sympathetic axons that project to the eye requires both activity-dependent BDNF and p75NTR. p75NTR and BDNF are also essential for activity-dependent axon pruning in culture, where they mediate pruning by directly causing axon degeneration. p75NTR, which is enriched in losing axons, causes axonal degeneration by suppressing TrkA-mediated signaling that is essential for axonal maintenance. These data provide a mechanism that explains how active axons can eliminate less-active, competing axons during developmental pruning by directly promoting p75NTR-mediated axonal degeneration.
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We thank members of the Miller/Kaplan laboratory for technical advice and assistance and M. Sendtner for helpful discussions. This work was supported by grants from the Canadian Institutes of Health Research (F.D.M. and D.R.K.) and the US National Institutes of Health (M.E.G.). K.K.S. and K.J.P. were supported by studentships from the Ontario Graduate Scholarship and the Hospital for Sick Children and B.M.K. by a fellowship from the Multiple Sclerosis Society of Canada. F.D.M. and D.R.K. are Canada Research Chairs, and F.D.M. is a Howard Hughes Medical Institute International Research Scholar.
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