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

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.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.06077-11.

ACKNOWLEDGMENTS

We thank Christopher Henderson and George Mentis for comments and critical reading of the manuscript. We are grateful to James Manley for the kind gift of SMN1 and SMN2 splicing reporter constructs and to Brunhilde Wirth for antibodies against Tra2-β1. We acknowledge the help of Mariangels de Planell Saguer with experiments in Fig. 3.

This work was supported by grants from the Spinal Muscular Atrophy Foundation (to L.P.) and NIH-NINDS R01NS069601 (to L.P.), R01NS057482 (to U.R.M.), and R01NS038650 (to A.H.M.B.). The National Center for Research Resources provided additional funding for LCM work (award no. UL1RR025755 to A.H.M.B.).

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