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p75NTR-dependent, myelin-mediated axonal degeneration regulates neural connectivity in the adult brain

Nature Neuroscience volume 13, pages 559–566 (2010)Cite this article

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Abstract

Axonal degeneration is important during development but has not been thought to function in the intact mature nervous system. Here, we provide evidence that degeneration of adult axons occurs in the intact rodent brain through a p75 neurotrophin receptor (p75NTR)- and myelin-dependent mechanism. Specifically, we show that p75NTR-mediated axonal degeneration prevents septal cholinergic axons from aberrantly growing onto myelinated tracts in vivo or on a myelin substrate in culture. Myelin also triggers local degeneration of p75NTR-expressing sympathetic axons that is rescued by increasing TrkA signaling or elevating intracellular cyclic AMP. Myelin-mediated degeneration occurs when neurotrophins bind to p75NTR, and involves p75NTR-dependent sequestration of Rho guanine nucleotide dissociation inhibitor (Rho-GDI). Moreover, degeneration, but not growth inhibition, requires downstream activation of Rho and caspase-6. These data indicate that p75NTR maintains the specificity of neural connectivity by preventing inappropriate sprouting onto myelinated tracts and provide a physiological explanation for myelin inhibition after neural injury.

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Figure 1: p75NTR inhibits the growth of septal cholinergic axons on the mature corpus callosum.
Figure 2: Myelin induces degeneration of septal cholinergic axons in low NGF in a p75NTR-dependent fashion.
Figure 3: Myelin induces local degeneration of sympathetic axons, and this can be rescued by high NGF or elevated intracellular cAMP.
Figure 4: Myelin-induced local sympathetic axon degeneration is p75NTR dependent.
Figure 5: Myelin-induced axonal degeneration requires neurotrophin binding to p75NTR.
Figure 6: p75NTR causes axonal degeneration through a Rho-GDI–Rho–caspase-6 pathway.

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Acknowledgements

We thank J. Laver for helping with the time-course degeneration experiments, members of the Miller/Kaplan laboratory, J. Atwal, K. Coultes, L. Weng and J. Jordao for advice and technical assistance and P. Barker (McGill University) for p75NTR adenovirus. This work was supported by a grant from the Canadian Institutes of Health Research to F.D.M. and D.R.K. F.D.M. and D.R.K. are supported by the Canada Research Chairs program and F.D.M. by the Howard Hughes Medical Institute. K.J.P. was supported by an Ontario Graduate Scholarship.

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Authors and Affiliations

  1. Developmental and Stem Cell Biology, Toronto, Ontario, Canada

    Katya J Park & Freda D Miller

  2. Cell Biology Programs, Hospital for Sick Children, Toronto, Ontario, Canada

    Katya J Park & David R Kaplan

  3. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    Katya J Park, David R Kaplan & Freda D Miller

  4. Sunnybrook Research Institute, Toronto, Ontario, Canada

    Carlos Ayala Grosso & Isabelle Aubert

  5. Facultad de Farmacia, Universidad Central de Venezuela, Caracas, Venezuela

    Carlos Ayala Grosso

  6. Departments of Laboratory Medicine and Pathobiology, Toronto, Ontario, Canada

    Isabelle Aubert

  7. Molecular Genetics, Toronto, Ontario, Canada

    David R Kaplan & Freda D Miller

  8. Physiology, University of Toronto, Toronto, Ontario, Canada

    Freda D Miller

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Contributions

K.J.P. carried out all experiments and co-wrote the paper. C.A.G. participated in the in vivo analysis. I.A. supervised the septal cholinergic experiments. D.R.K. and F.D.M. co-supervised all experiments and co-wrote the paper.

Corresponding authors

Correspondence to David R Kaplan or Freda D Miller.

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Park, K., Grosso, C., Aubert, I. et al. p75NTR-dependent, myelin-mediated axonal degeneration regulates neural connectivity in the adult brain. Nat Neurosci 13, 559–566 (2010). https://doi.org/10.1038/nn.2513

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