Molecular mechanisms and animal models of spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is characterized by the degeneration of spinal motor neurons and muscle atrophy. Although the genetic cause of SMA has been mapped to the Survival Motor Neuron1 (SMN1) gene, mechanisms underlying selective motor neuron degeneration in SMA remain largely unknown. Here we review the latest developments and our current understanding of the molecular mechanisms underlying SMA pathogenesis, focusing on the animal model systems that have been developed, as well as new diagnostic and treatment strategies that have been identified using these model systems. This article is part of a special issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

Keywords: Animal disease models; C. elegans; Drosophila; SMA; SMN; Zebrafish.

Fig. 1.

SMN protein sequence and function are conserved across species during evolution. A. Phylogenetic tree based on SMN protein sequence showing the genetic divergence among SMN from different species using the neighbor joining method. B. Amino acid sequence alignment of SMN proteins from different organisms. Identical and similar amino acids are outlined.

Fig. 2.

Defects in SMA model systems represent different aspects of disease pathogenesis. A– C. Morpholino antisense oligonucleotide knockdown of smn in zebrafish leads to truncation or ectopic branching (white arrow heads in B) of motor axons in Tg(olig2:egfp) embryos 28 hours post fertilization. Boxed area in A is shown in B and C. D–G. The number of lumbar level spinal motor neurons recognized by the anti-HB9 antibody (red) is reduced by ~50% in SMA Δ7 mice compared to wild type littermates at postnatal day 9. Motor neurons affected by SMA show swollen morphology before dying. H–I. The number of glutamatergic excitatory synapses (green) on spinal motor neurons (red) is reduced by ~40% in SMA Δ7 mice at postnatal day 9. Glutamatergic synapses are shown by immunostaining with the anti-vGlut1 (vesicular glutamate transporters1) antibody, and spinal motor neurons are identified by immunostaining with the anti-ChAT (choline acetyltransferase) antibody. J-M. The number of motor neurons differentiated from SMA iPS cells is significantly less compared to wild type iPS cells. Human iPS cells generated from SMA patient skin fibroblasts differentiate into spinal motor neurons after 4–6 weeks of development. Brightfield microscopy (J) and immunofluorescence staining (K-M) are used to show undifferentiated iPS cells (J-K) expressing the pluripotency marker Oct4 (green in K), iPS cell-derived motor neurons (L-M) coexpressing neuronal marker TuJ1 (green in L, M) and the motor neuron marker Isl1 (red in L, M). The number of Isl1 positive motor neurons as a percentage of all TuJ1 positive neurons from SMA iPS cells (M) is significantly less than those from wild type (WT) iPS cells (L).