Expanded genetic screening in Caenorhabditis elegans identifies new regulators and an inhibitory role for NAD + in axon regeneration

• Published in: eLife 2018-11, Vol.7
• Main Authors: Kim, Kyung Won, Tang, Ngang Heok, Piggott, Christopher A, Andrusiak, Matthew G, Park, Seungmee, Zhu, Ming, Kurup, Naina, Cherra, 3rd, Salvatore J, Wu, Zilu, Chisholm, Andrew D, Jin, Yishi
• Format: Article
• Language: English
• Subjects: Actin; Actin Cytoskeleton - metabolism; Actin Cytoskeleton - ultrastructure; Adenine; Algorithms; Animals; axon reconnection/fusion; Axons - metabolism; Axons - ultrastructure; Axotomy; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; CRISPR; Cytoskeleton; DNA polymerase; Enzymatic activity; Extracellular matrix; Extracellular Matrix - chemistry; Extracellular Matrix - metabolism; Gene Expression Profiling; Gene Expression Regulation; Gene Ontology; Genes; Genetic screening; Genetic Testing; Kelch Repeat; Kelch-domain protein; Lasers; membrane contact site (MCS); Membrane trafficking; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; membrane transporter; Microscopy; Microtubules - metabolism; Microtubules - ultrastructure; Molecular Sequence Annotation; Mutation; NAD; NAD - metabolism; Nematodes; Nerve Regeneration - genetics; Nervous system; Neuroscience; Neurosciences; Nicotinamide; Nicotinamide-Nucleotide Adenylyltransferase - genetics; Nicotinamide-Nucleotide Adenylyltransferase - metabolism; NMNAT; Peptides; phospholipid metabolic enzyme; Proteins; Regeneration; Software; Statistical analysis; Tools and Resources
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.39756

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 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.