Neuromuscular defects and breathing disorders in a new mouse model of spinal muscular atrophy

Neurobiol Dis. 2010 Apr;38(1):125-35. doi: 10.1016/j.nbd.2010.01.006. Epub 2010 Jan 18.

Abstract

Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein leading to muscle paralysis and respiratory failure. In mouse, introducing the human SMN2 gene partially rescues Smn(-)(/)(-) embryonic lethality. However current models were either too severe or nearly unaffected precluding convenient drug testing for SMA. We report here new SMN2;Smn(-/-) lines carrying one to four copies of the human SMN2 gene. Mice carrying three SMN2 copies exhibited an intermediate phenotype with delayed appearance of motor defects and developmental breathing disorders reminiscent of those found in severe SMA patients. Although normal at birth, at 7 days of age respiratory rate was decreased and apnea frequency was increased in SMA mice in parallel with the appearance of neuromuscular junction defects in the diaphragm. With median survival of 15 days and postnatal onset of neurodegeneration, these mice could be an important tool for evaluating new therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diaphragm / innervation
  • Diaphragm / physiopathology
  • Disease Models, Animal
  • Disease Progression
  • Genes, Lethal / physiology
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Mice
  • Mice, Transgenic
  • Muscular Atrophy, Spinal / genetics
  • Muscular Atrophy, Spinal / metabolism
  • Muscular Atrophy, Spinal / physiopathology*
  • Neuromuscular Junction / genetics
  • Neuromuscular Junction / metabolism
  • Neuromuscular Junction / pathology
  • Neuromuscular Junction Diseases / genetics
  • Neuromuscular Junction Diseases / metabolism
  • Neuromuscular Junction Diseases / physiopathology*
  • Respiratory Insufficiency / genetics
  • Respiratory Insufficiency / metabolism
  • Respiratory Insufficiency / physiopathology
  • Respiratory Paralysis / genetics
  • Respiratory Paralysis / metabolism
  • Respiratory Paralysis / physiopathology*
  • Survival of Motor Neuron 2 Protein / genetics

Substances

  • SMN2 protein, human
  • Survival of Motor Neuron 2 Protein