Developmental axon pruning mediated by BDNF-p75NTR–dependent axon degeneration

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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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Figure 1: Pruning of sympathetic eye-projecting axons requires p75NTR and activity-dependent synthesis of BDNF.
Figure 2: Eye-projecting sympathetic axons show degeneration during axon pruning.
Figure 3: BDNF-mediated p75NTR activation causes axon degeneration.
Figure 4: p75NTR regulates sympathetic axon competition in vitro.
Figure 5: p75NTR mediates degeneration of competing sympathetic axons.
Figure 6: p75NTR is preferentially localized to competing, degenerating axons.
Figure 7: The extent of degeneration of competing axons is a function of TrkA activation.
Figure 8: p75NTR mediates axon degeneration by suppressing TrkA-mediated signaling pathways.

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Acknowledgements

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 information

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.

Correspondence to Freda D Miller.

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Singh, K., Park, K., Hong, E. et al. Developmental axon pruning mediated by BDNF-p75NTR–dependent axon degeneration. Nat Neurosci 11, 649–658 (2008) doi:10.1038/nn.2114

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