Tissue-specific models of spinal muscular atrophy confirm a critical role of SMN in motor neurons from embryonic to adult stages

Laird, A.S., Mackovski, N., Rinkwitz, S., Becker, T.S., Giacomotto, J.
Human molecular genetics   25(9): 1728-38 (Journal)
Registered Authors
Becker, Thomas S., Giacomotto, Jean, Laird, Angela, Rinkwitz, Silke
MeSH Terms
  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Embryo, Nonmammalian/cytology*
  • Embryo, Nonmammalian/metabolism
  • Gene Expression Regulation, Developmental
  • Humans
  • MicroRNAs/genetics*
  • Motor Neurons/metabolism
  • Motor Neurons/pathology*
  • Muscle, Skeletal/metabolism
  • Muscle, Skeletal/pathology*
  • Muscular Atrophy, Spinal/metabolism*
  • Muscular Atrophy, Spinal/pathology*
  • Survival of Motor Neuron 1 Protein/antagonists & inhibitors
  • Survival of Motor Neuron 1 Protein/genetics
  • Survival of Motor Neuron 1 Protein/metabolism*
  • Zebrafish
26908606 Full text @ Hum. Mol. Genet.
Spinal Muscular Atrophy (SMA) is an autosomal recessive disease linked to SMN protein deficiency. While SMN protein is expressed ubiquitously, its deficiency triggers tissue-specific hallmarks, including motor neuron death and muscle atrophy, leading to impaired motor functions and premature death. Here, using stable miR-mediated knockdown technology in zebrafish, we developed the first vertebrate system allowing transgenic spatio-temporal control of the smn1 gene. Using this new model it is now possible to investigate normal and pathogenic SMN function(s) in specific cell types, independently or in synergy with other cell populations. We took advantage of this new system to first test the effect of motor neuron or muscle-specific smn1-silencing. Anti-smn1 miRNA expression in motor neurons, but not in muscles, reproduced SMA hallmarks, including abnormal motor neuron development, poor motor function, and premature death. Interestingly, smn1-knockdown in motor neurons also induced severe late-onset phenotypes including scoliosis-like body deformities, weight loss, muscle atrophy and, seen for the first time in zebrafish, reduction in the number of motor neurons, indicating motor neuron degeneration. Taken together, we have developed a new transgenic system allowing spatio-temporal control of smn1 expression in zebrafish, and using this model, we have demonstrated that smn1-silencing in motor neurons alone is sufficient to reproduce SMA hallmarks in zebrafish. It is noteworthy that this research is going beyond SMA as this versatile gene-silencing transgenic system can be used to knockdown any genes of interest, filling the gap in the zebrafish genetic toolbox and opening new avenues to study gene functions in this organism.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes