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The growth factor SVH-1 regulates axon regeneration in C. elegans via the JNK MAPK cascade

Nature Neuroscience volume 15, pages 551–557 (2012)Cite this article

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Abstract

The ability of neurons to undergo regenerative growth after injury is governed by cell-intrinsic and cell-extrinsic regeneration pathways. These pathways represent potential targets for therapies to enhance regeneration. However, the signaling pathways that orchestrate axon regeneration are not well understood. In Caenorhabditis elegans, the Jun N-terminal kinase (JNK) and p38 MAP kinase (MAPK) pathways are important for axon regeneration. We found that the C. elegans SVH-1 growth factor and its receptor, SVH-2 tyrosine kinase, regulate axon regeneration. Loss of SVH-1–SVH-2 signaling resulted in a substantial defect in the ability of neurons to regenerate, whereas its activation improved regeneration. Furthermore, SVH-1–SVH-2 signaling was initiated extrinsically by a pair of sensory neurons and functioned upstream of the JNK-MAPK pathway. Thus, SVH-1–SVH-2 signaling via activation of the MAPK pathway acts to coordinate neuron regeneration response after axon injury.

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Figure 1: SVH-1 and SVH-2 are required for axon regeneration in C. elegans.
Figure 2: Expression patterns of the svh-1 and svh-2 genes.
Figure 3: Relationship between svh-1 and svh-2 in axon regeneration.
Figure 4: Effects of overexpression of svh-1 and svh-2 on axon regeneration.
Figure 5: SVH-2 functions in the JNK pathway.

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Acknowledgements

We thank Y. Kohara, S. Mitani, the Caenorhabditis Genetic Center and the C. elegans Knockout Consortium for materials. This work was supported by grants from Ministry of Education, Culture and Science of Japan, the Sumitomo Foundation (to K.M., T.M. and N.H.), the Nakajima Science Foundation (to T.M.), the National Science Foundation, the McKnight Endowment Fund for Neuroscience, the Christopher and Dana Reeve Foundation, and the Amerisure Charitable Foundation (to M.B. and P.N.). C.L. was supported by a Japan Society for the Promotion of Science Research Fellowship.

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Author notes

  1. Tomoaki Mizuno

    Present address: Present address: Department of Molecular Cell Biology, Graduate School of Comprehensive Human Studies, University of Tsukuba, Tsukuba, Japan.,

  2. Chun Li and Naoki Hisamoto: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya, Japan

    Chun Li, Naoki Hisamoto, Shuka Kanao, Tomoaki Mizuno & Kunihiro Matsumoto

  2. Department of Biology, University of Utah, Salt Lake City, Utah, USA

    Paola Nix & Michael Bastiani

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  1. Chun Li
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Contributions

C.L., N.H., P.N., M.B. and K.M. designed the experiments and analyzed data. S.K. and T.M. performed the biochemical experiments. P.N. and M.B. carried out the time-lapse experiments. C.L. and N.H. performed all of the other experiments. The manuscript was written by K.M. and commented on by N.H., P.N. and M.B.

Corresponding authors

Correspondence to Naoki Hisamoto or Kunihiro Matsumoto.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 and Supplementary Tables 1 and 2 (PDF 9979 kb)

Supplementary Video 1

Time-lapse image of severed axon of D-type motor neuron in wild-type animal. (MOV 11031 kb)

Supplementary Video 2

Time-lapse image of severed axon of D-type motor neuron in svh-2 mutant animal. (MOV 1558 kb)

Supplementary Video 3

Time-lapse image of severed axon of D-type motor neuron in svh-2 mutant animal. (MOV 2953 kb)

Supplementary Video 4

Time-lapse image of severed axon of D-type motor neuron in svh-1 mutant animal. (MOV 453 kb)

Supplementary Video 5

Time-lapse image of severed axon of D-type motor neuron in svh-1-overexpressing animal. (MOV 10209 kb)

Supplementary Video 6

Time-lapse image of severed axon of D-type motor neuron in svh-2-overexpressing animal. (MOV 8468 kb)

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Li, C., Hisamoto, N., Nix, P. et al. The growth factor SVH-1 regulates axon regeneration in C. elegans via the JNK MAPK cascade. Nat Neurosci 15, 551–557 (2012). https://doi.org/10.1038/nn.3052

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