The secreted MSP domain of C. elegans VAPB homolog VPR-1 patterns the adult striated muscle mitochondrial reticulum via SMN-1

Development. 2017 Jun 15;144(12):2175-2186. doi: 10.1242/dev.152025.


The major sperm protein domain (MSPd) has an extracellular signaling function implicated in amyotrophic lateral sclerosis. Secreted MSPds derived from the C. elegans VAPB homolog VPR-1 promote mitochondrial localization to actin-rich I-bands in body wall muscle. Here we show that the nervous system and germ line are key MSPd secretion tissues. MSPd signals are transduced through the CLR-1 Lar-like tyrosine phosphatase receptor. We show that CLR-1 is expressed throughout the muscle plasma membrane, where it is accessible to MSPd within the pseudocoelomic fluid. MSPd signaling is sufficient to remodel the muscle mitochondrial reticulum during adulthood. An RNAi suppressor screen identified survival of motor neuron 1 (SMN-1) as a downstream effector. SMN-1 acts in muscle, where it colocalizes at myofilaments with ARX-2, a component of the Arp2/3 actin-nucleation complex. Genetic studies suggest that SMN-1 promotes Arp2/3 activity important for localizing mitochondria to I-bands. Our results support the model that VAPB homologs are circulating hormones that pattern the striated muscle mitochondrial reticulum. This function is crucial in adults and requires SMN-1 in muscle, likely independent of its role in pre-mRNA splicing.

Keywords: ALS; Amyotrophic lateral sclerosis; MSP; Major sperm protein domain; Mitochondria; SMA; SMN-1; Spinal muscular atrophy; Striated muscle; VAPA; VAPB.

Publication types

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

MeSH terms

  • Actin-Related Protein 2 / metabolism
  • Actin-Related Protein 2-3 Complex / metabolism
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / growth & development*
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Genes, Helminth
  • Germ Cells / metabolism
  • Humans
  • Larva / growth & development
  • Larva / metabolism
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mitochondria, Muscle / metabolism
  • Motor Neurons / metabolism
  • Muscle, Striated / growth & development*
  • Muscle, Striated / metabolism*
  • Mutation
  • Protein Domains
  • RNA Interference
  • Receptor-Like Protein Tyrosine Phosphatases / genetics
  • Receptor-Like Protein Tyrosine Phosphatases / metabolism
  • SMN Complex Proteins / antagonists & inhibitors
  • SMN Complex Proteins / genetics
  • SMN Complex Proteins / metabolism*
  • Sarcolemma / metabolism
  • Signal Transduction


  • Actin-Related Protein 2
  • Actin-Related Protein 2-3 Complex
  • Caenorhabditis elegans Proteins
  • Membrane Proteins
  • SMN Complex Proteins
  • VPR-1 protein, C elegans
  • arx-2 protein, C elegans
  • CLR-1 protein, C elegans
  • Receptor-Like Protein Tyrosine Phosphatases