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.
Digital Object Identifier (DOI)
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).
Figure 1. Source data 1. DOI: https://doi.org/10.7554/eLife.39756.006
Figure 1. Figure supplement 1. DOI: https://doi.org/10.7554/eLife.39756.003
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
Figure 2. Source data 1. DOI: https://doi.org/10.7554/eLife.39756.011
Figure 2. Figure supplement 1. DOI: https://doi.org/10.7554/eLife.39756.010
Figure 3. Source data 1. DOI: https://doi.org/10.7554/eLife.39756.014
Figure 3. Figure supplement 1. DOI: https://doi.org/10.7554/eLife.39756.013
Figure 4. Source data 1. DOI: https://doi.org/10.7554/eLife.39756.016
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.
Kim, Kyung Won; Tang, Ngana Heok; Piggott, Christopher A.; Andrusiak, Matthew G.; Park, Seungmee; Zhu, Ming; Kurup, Naina; Cherra, Salvatore J. III; Wu, Zilu; Chisholm, Andrew D.; and Jin, Yishi, "Expanded Genetic Screening in Caenorhabditis elegans Identifies New Regulators and an Inhibitory Role for NAD+ in Axon Regeneration" (2018). Neuroscience Faculty Publications. 53.
Figure 1—source data 1.
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Transparent reporting form.