Secreted VAPB/ALS8 major sperm protein domains modulate mitochondrial localization and morphology via growth cone guidance receptors

Dev Cell. 2012 Feb 14;22(2):348-62. doi: 10.1016/j.devcel.2011.12.009. Epub 2012 Jan 19.


The VAPB/ALS8 major sperm protein domain (vMSP) is implicated in amyotrophic lateral sclerosis and spinal muscular atrophy, yet its function in the nervous system is not well understood. In Caenorhabditis elegans and Drosophila, the vMSP is cleaved from its transmembrane anchor and secreted in a cell type-specific fashion. We show that vMSPs secreted by neurons act on Lar-like protein-tyrosine phosphatase and Roundabout growth cone guidance receptors expressed in striated muscle. This signaling pathway promotes Arp2/3-dependent actin remodeling and mitochondrial localization to actin-rich muscle I-bands. C. elegans VAPB mutants have mitochondrial localization, morphology, mobility, and fission/fusion defects that are suppressed by Lar-like receptor or Arp2/3 inactivation. Hence, growth cone guidance receptor pathways that remodel the actin cytoskeleton have unanticipated effects on mitochondrial dynamics. We propose that neurons secrete vMSPs to promote striated muscle energy production and metabolism, in part through the regulation of mitochondrial localization and function.

Publication types

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

MeSH terms

  • Actin-Related Protein 2-3 Complex / metabolism
  • Actins / metabolism
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / growth & development
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Fluorescence
  • Growth Cones / metabolism*
  • Helminth Proteins / genetics
  • Helminth Proteins / metabolism*
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Muscle, Striated / cytology
  • Muscle, Striated / metabolism*
  • Neurons / cytology
  • Neurons / metabolism*
  • Protein Structure, Tertiary
  • Signal Transduction
  • Transgenes / physiology


  • Actin-Related Protein 2-3 Complex
  • Actins
  • Caenorhabditis elegans Proteins
  • Helminth Proteins
  • major sperm protein, nematode