Specific proteolytic cleavage of agrin regulates maturation of the neuromuscular junction

J Cell Sci. 2010 Nov 15;123(Pt 22):3944-55. doi: 10.1242/jcs.072090. Epub 2010 Oct 27.


During the initial stage of neuromuscular junction (NMJ) formation, nerve-derived agrin cooperates with muscle-autonomous mechanisms in the organization and stabilization of a plaque-like postsynaptic specialization at the site of nerve-muscle contact. Subsequent NMJ maturation to the characteristic pretzel-like appearance requires extensive structural reorganization. We found that the progress of plaque-to-pretzel maturation is regulated by agrin. Excessive cleavage of agrin via transgenic overexpression of an agrin-cleaving protease, neurotrypsin, in motoneurons resulted in excessive reorganizational activity of the NMJs, leading to rapid dispersal of the synaptic specialization. By contrast, expression of cleavage-resistant agrin in motoneurons slowed down NMJ remodeling and delayed NMJ maturation. Neurotrypsin, which is the sole agrin-cleaving protease in the CNS, was excluded as the physiological agrin-cleaving protease at the NMJ, because NMJ maturation was normal in neurotrypsin-deficient mice. Together, our analyses characterize agrin cleavage at its proteolytic α- and β-sites by an as-yet-unspecified protease as a regulatory access for relieving the agrin-dependent constraint on endplate reorganization during NMJ maturation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agrin / metabolism*
  • Animals
  • Cell Line
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Transgenic
  • Motor Neurons / metabolism
  • Nerve Fibers / metabolism
  • Neuromuscular Junction / metabolism*
  • Serine Endopeptidases / biosynthesis
  • Serine Endopeptidases / metabolism*
  • Spinal Cord / cytology
  • Synaptic Transmission / physiology


  • Agrin
  • Serine Endopeptidases
  • neurotrypsin