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The MAP kinase phosphatase MKP-1 regulates BDNF-induced axon branching

Nature Neuroscience volume 13, pages 1373–1379 (2010)Cite this article

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Abstract

The refinement of neural circuits during development depends on a dynamic process of branching of axons and dendrites that leads to synapse formation and connectivity. The neurotrophin brain-derived neurotrophic factor (BDNF) is essential for the outgrowth and activity-dependent remodeling of axonal arbors in vivo. However, the mechanisms that translate extracellular signals into the formation of axonal branches are incompletely understood. We found that MAP kinase phosphatase-1 (MKP-1) controls axon branching. MKP-1 expression induced by BDNF signaling caused spatiotemporal deactivation of c-jun N-terminal kinase (JNK), which reduced the phosphorylation of JNK substrates that destabilize microtubules. Indeed, neurons from mkp-1 null mice could not produce axon branches in response to BDNF. Our results identify a signaling mechanism that regulates axonal branching and provide a framework for studying the molecular mechanisms of innervation and axonal remodeling under normal and pathological conditions.

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Figure 1: Gain- and loss-of-function of MKP-1 in vivo affect neural development.
Figure 2: JNK is the MKP-1 substrate that alters axonal morphology.
Figure 3: Induction of MKP-1 expression by BDNF.
Figure 4: BDNF controls MKP-1 expression in a spatiotemporal manner.
Figure 5: MKP-1 mediates BDNF-induced axon branching.

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Acknowledgements

This research was supported by the National Alliance for Research on Schizophrenia and Depression (F.J. and G.M.), the Human Frontier Science Program Organization (K.D.) and grants from the US National Institutes of Health to M.V.C. (NS21072 and HD23315) and A.M.B. (R01 AR46504).

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Author notes

  1. Freddy Jeanneteau and Katrin Deinhardt: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, New York, New York, USA

    Freddy Jeanneteau, Katrin Deinhardt & Moses V Chao

  2. Smilow Neuroscience Program, New York University Langone School of Medicine, New York, New York, USA

    Goichi Miyoshi

  3. Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA

    Anton M Bennett

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  1. Freddy Jeanneteau
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Contributions

F.J. and K.D. designed, performed and analyzed experiments. F.J., K.D. and M.V.C. wrote the manuscript. G.M. helped with the in utero electroporations. G.M. and A.M.B. provided mice and reagents.

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Correspondence to Freddy Jeanneteau or Katrin Deinhardt.

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Jeanneteau, F., Deinhardt, K., Miyoshi, G. et al. The MAP kinase phosphatase MKP-1 regulates BDNF-induced axon branching. Nat Neurosci 13, 1373–1379 (2010). https://doi.org/10.1038/nn.2655

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