Shift from extracellular signal-regulated kinase to AKT/cAMP response element-binding protein pathway increases survival-motor-neuron expression in spinal-muscular-atrophy-like mice and patient cells

J Neurosci. 2013 Mar 6;33(10):4280-94. doi: 10.1523/JNEUROSCI.2728-12.2013.


Spinal muscular atrophy (SMA), a recessive neurodegenerative disease, is characterized by the selective loss of spinal motor neurons. No available therapy exists for SMA, which represents one of the leading genetic causes of death in childhood. SMA is caused by a mutation of the survival-of-motor-neuron 1 (SMN1) gene, leading to a quantitative defect in the survival-motor-neuron (SMN) protein expression. All patients retain one or more copies of the SMN2 gene, which modulates the disease severity by producing a small amount of stable SMN protein. We reported recently that NMDA receptor activation, directly in the spinal cord, significantly enhanced the transcription rate of the SMN2 genes in a mouse model of very severe SMA (referred as type 1) by a mechanism that involved AKT/CREB pathway activation. Here, we provide the first compelling evidence for a competition between the MEK/ERK/Elk-1 and the phosphatidylinositol 3-kinase/AKT/CREB signaling pathways for SMN2 gene regulation in the spinal cord of type 1 SMA-like mice. The inhibition of the MEK/ERK/Elk-1 pathway promotes the AKT/CREB pathway activation, leading to (1) an enhanced SMN expression in the spinal cord of SMA-like mice and in human SMA myotubes and (2) a 2.8-fold lifespan extension in SMA-like mice. Furthermore, we identified a crosstalk between ERK and AKT signaling pathways that involves the calcium-dependent modulation of CaMKII activity. Together, all these data open new perspectives to the therapeutic strategy for SMA patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Butadienes / pharmacology
  • Calcium / metabolism
  • Cell Survival / physiology
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Coculture Techniques / methods
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agonists / pharmacology
  • Exploratory Behavior / drug effects
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Ganglia, Spinal / cytology
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Motor Neurons / drug effects
  • Motor Neurons / pathology
  • Motor Neurons / physiology*
  • Muscle Cells / drug effects
  • Muscle Cells / physiology
  • Muscular Atrophy, Spinal / pathology*
  • N-Methylaspartate / pharmacology
  • Nitriles / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Stem Cells / drug effects
  • Stem Cells / physiology
  • Survival of Motor Neuron 2 Protein / deficiency


  • Butadienes
  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Nitriles
  • Survival of Motor Neuron 2 Protein
  • U 0126
  • N-Methylaspartate
  • Extracellular Signal-Regulated MAP Kinases
  • Calcium