The mechanisms underlying axon regeneration in mature neurons are relevant to the understanding of normal nervous system maintenance and for developing therapeutic strategies for injury. Here, we report novel pathways in axon regeneration, identified by extending our previous function-based screen using the C. elegans mechanosensory neuron axotomy model. We identify an unexpected role of the nicotinamide adenine dinucleotide (NAD+) synthesizing enzyme, NMAT-2/NMNAT, in axon regeneration. NMAT-2 inhibits axon regrowth via cell-autonomous and non-autonomous mechanisms. NMAT-2 enzymatic activity is required to repress regrowth. Further, we find differential requirements for proteins in membrane contact site, components and regulators of the extracellular matrix, membrane trafficking, microtubule and actin cytoskeleton, the conserved Kelch-domain protein IVNS-1, and the orphan transporter MFSD-6 in axon regrowth. Identification of these new pathways expands our understanding of the molecular basis of axonal injury response and regeneration.

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Published in eLife, v. 7, e39756, p. 1-31.

© 2018, Kim et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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Funding Information

We thank Dr. S Mitani and National Bioresource Project of Japan, and the Caenorhabditis Genetics Center (funded by NIH Office of Research Infrastructure Programs P40 OD010440) for strains. KWK received an American Heart Association postdoctoral fellowship and Hallym University research funds (HRF-201809–014), MGA received a Canadian Institutes of Health Research Postdoctoral Fellowship (MFE-146808), and SJC was a receipient of NIH K99 (NS097638). This work was supported by NIH R01 grants to YJ, and ADC (NS057317 and NS093588).

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Figure 1. Source data 1. DOI: https://doi.org/10.7554/eLife.39756.006

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Figure 1. Figure supplement 2. DOI: https://doi.org/10.7554/eLife.39756.004

Figure 1. Figure supplement 2—source data 1. DOI: https://doi.org/10.7554/eLife.39756.005

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Figure 5. Source data 1. DOI: https://doi.org/10.7554/eLife.39756.018

Transparent reporting form. DOI: https://doi.org/10.7554/eLife.39756.019

All data generated or analysed during this study are included in the manuscript and supporting files.

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Figure 1—source data 1.

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Figure 1—figure supplement 1.

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Figure 1—figure supplement 2.

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Figure 1—figure supplement 2—source data 1.

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Figure 2—source data 1.

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Figure 2—figure supplement 1.

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Figure 3—source data 1.

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Figure 3—figure supplement 1.

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Figure 5—source data 1.

elife-39756-transrepform-v2.docx (246 kB)
Transparent reporting form.