Singh, Karun K. and Park, Katya J. and Hong, Elizabeth J. and Kramer, Bianca M. and Greenberg, Michael E. and Kaplan, David R. and Miller, Freda D. (2008) Developmental axon pruning mediated by BDNF-p75NTR–dependent axon degeneration. Nature Neuroscience, 11 (6). pp. 649-658. ISSN 1097-6256. doi:10.1038/nn.2114. https://resolver.caltech.edu/CaltechAUTHORS:20151005-162305172
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Abstract
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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| Additional Information: | © 2008 Macmillan Publishers Limited. Received 13 March 2008; accepted 25 March 2008; published online 1 April 2008; doi:10.1038/nn.2114 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. Author contributions: K.K.S. carried out all of the experiments except for the iris analysis and the p75NTR signaling experiments, and co-wrote the paper. K.J.P. performed the iris analysis and K.J.P. and B.M.K. carried out the p75NTR signaling experiments. E.J.H. made the BDNF promoter mutant mice, and worked with K.K.S. on KCl-mediated induction of BDNF mRNA and analysis of eye-projecting neurons in these mice. M.E.G. supervised construction of the BDNF promoter mutant mice and the gene expression analyses, and D.R.K. supervised the biochemical experiments. F.D.M. supervised or co-supervised all of the experiments and co-wrote the paper. | ||||||||||||||||
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| Issue or Number: | 6 | ||||||||||||||||
| DOI: | 10.1038/nn.2114 | ||||||||||||||||
| Record Number: | CaltechAUTHORS:20151005-162305172 | ||||||||||||||||
| Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:20151005-162305172 | ||||||||||||||||
| Official Citation: | Developmental axon pruning mediated by BDNF-p75NTR–dependent axon degeneration Karun K Singh, Katya J Park, Elizabeth J Hong, Bianca M Kramer, Michael E Greenberg, David R Kaplan & Freda D Miller Nature Neuroscience 11, 649 - 658 (2008) Published online: 1 April 2008 | doi:10.1038/nn.2114 | ||||||||||||||||
| Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||||||||||||
| ID Code: | 60787 | ||||||||||||||||
| Collection: | CaltechAUTHORS | ||||||||||||||||
| Deposited By: | George Porter | ||||||||||||||||
| Deposited On: | 05 Oct 2015 23:52 | ||||||||||||||||
| Last Modified: | 10 Nov 2021 22:39 |
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