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

Elife. 2018 Nov 21:7:e39756. doi: 10.7554/eLife.39756.

Abstract

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.

Keywords: C. elegans; Kelch-domain protein; NMNAT; axon reconnection/fusion; membrane contact site (MCS); membrane transporter; neuroscience; phospholipid metabolic enzyme.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Actin Cytoskeleton / ultrastructure
  • Animals
  • Axons / metabolism*
  • Axons / ultrastructure
  • Axotomy
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics*
  • Caenorhabditis elegans Proteins / metabolism
  • Extracellular Matrix / chemistry
  • Extracellular Matrix / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Ontology
  • Genetic Testing
  • Kelch Repeat
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Microtubules / metabolism
  • Microtubules / ultrastructure
  • Molecular Sequence Annotation
  • NAD / metabolism*
  • Nerve Regeneration / genetics*
  • Nicotinamide-Nucleotide Adenylyltransferase / genetics*
  • Nicotinamide-Nucleotide Adenylyltransferase / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • Membrane Transport Proteins
  • NAD
  • Nicotinamide-Nucleotide Adenylyltransferase