A role for SMN exon 7 splicing in the selective vulnerability of motor neurons in spinal muscular atrophy.
Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by homozygous loss of the Survival Motor Neuron 1 (SMN1) gene. In the absence of SMN1, inefficient inclusion of exon 7 in transcripts from the nearly identical SMN2 gene results in ubiquitous SMN decrease but selective motor neuron degeneration. Here we investigated whether cell type-specific differences in the efficiency of exon 7 splicing contribute to the vulnerability of SMA motor neurons. We show that normal motor neurons express markedly lower levels of full-length SMN mRNA from SMN2 than do other cells in the spinal cord. This is due to inefficient exon 7 splicing that is intrinsic to motor neurons under normal conditions. We also find that SMN depletion in mammalian cells decreases exon 7 inclusion through a negative feedback loop affecting the splicing of its own mRNA. This mechanism is active in vivo and further decreases the efficiency of exon 7 inclusion specifically in motor neurons of severe-SMA mice. Consistent with expression of lower levels of full-length SMN, we find that SMN-dependent downstream molecular defects are exacerbated in SMA motor neurons. These findings suggest a mechanism to explain the selective vulnerability of motor neurons to loss of SMN1.
Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.
Matteo
M
Ruggiu
Vicki L
VL
McGovern
Francesco
F
Lotti
Luciano
L
Saieva
Darrick K
DK
Li
Shingo
S
Kariya
Umrao R
UR
Monani
Arthur H M
AH
Burghes
Livio
L
Pellizzoni
D000818:Animals; D005091:Exons; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D041681:NIH 3T3 Cells; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics; D055532:SMN Complex Proteins / Q000235:genetics*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
D012333:RNA, Messenger; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein