A Role for SMN Exon 7 Splicing in the Selective Vulnerability of Motor Neurons in Spinal Muscular Atrophy

Author:

Ruggiu Matteo12,McGovern Vicki L.3,Lotti Francesco12,Saieva Luciano12,Li Darrick K.12,Kariya Shingo124,Monani Umrao R.124,Burghes Arthur H. M.3,Pellizzoni Livio12

Affiliation:

1. Department of Pathology and Cell Biology, Columbia University, New York, New York, USA

2. Center for Motor Neuron Biology and Disease, Columbia University, New York, New York, USA

3. Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio, USA

4. Department of Neurology, Columbia University, New York, New York, USA

Abstract

ABSTRACT 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 .

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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