Many neurogenetic disorders are caused by the mutation of ubiquitously expressed genes. Spinal muscular atrophy is one such disorder and is caused by loss or mutation of the survival motor neuron 1 gene (SMN1), leading to reduced SMN protein levels and a selective dysfunction of motor neurons. SMN, in collaboration with partner proteins, functions in the assembly of small nuclear ribonucleoproteins (snRNPs), which are important for pre-mRNA splicing. It has also been suggested that SMN might function in the assembly of other RNP complexes. Two hypotheses have been proposed to explain the molecular dysfunction that gives rise to SMA and its specificity to a particular group of neurons. The first hypothesis states that the loss of SMN's well-known function in snRNP assembly causes an alteration in the splicing of a specific gene (or genes). A second hypothesis proposes that SMN is critical for the transport of mRNA in neurons and disruption of this function results in SMA.

Homozygous deletion of the survival motor neuron 1 gene (SMN1) causes spinal muscular atrophy (SMA), the most frequent genetic cause of early childhood lethality. In rare instances, however, individuals are asymptomatic despite carrying the same SMN1 mutations as their affected siblings, thereby suggesting the influence of modifier genes. We discovered that unaffected SMN1-deleted females exhibit significantly higher expression of plastin 3 (PLS3) than their SMA-affected counterparts. We demonstrated that PLS3 is important for axonogenesis through increasing the F-actin level. Overexpression of PLS3 rescued the axon length and outgrowth defects associated with SMN down-regulation in motor neurons of SMA mouse embryos and in zebrafish. Our study suggests that defects in axonogenesis are the major cause of SMA, thereby opening new therapeutic options for SMA and similar neuromuscular diseases.

SUMMARY Spinal muscular atrophy (SMA) is a motor neuron disease caused by deficiency of the ubiquitous survival motor neuron (SMN) protein. To define the mechanisms of selective neuronal dysfunction in SMA, we investigated the role of SMN-dependent U12 splicing events in the regulation of motor circuit activity. We show that SMN deficiency perturbs splicing and decreases the expression of a subset of U12 intron-containing genes in mammalian cells and Drosophila larvae. Analysis of these SMN target genes identifies Stasimon as a novel protein required for motor circuit function. Restoration of Stasimon expression in the motor circuit corrects defects in neuromuscular junction transmission and muscle growth in Drosophila SMN mutants and aberrant motor neuron development in SMN-deficient zebrafish. These findings directly link defective splicing of critical neuronal genes induced by SMN deficiency to motor circuit dysfunction, establishing a molecular framework for the selective pathology of SMA.