The survival motor neuron gene <i>smn-1</i> interacts with the U2AF large subunit gene <i>uaf-1</i> to regulate <i>Caenorhabditis elegans</i> lifespan and motor functions

Spinal muscular atrophy (SMA), the most frequent human congenital motor neuron degenerative disease, is caused by loss-of-function mutations in the highly conserved survival motor neuron gene <i>SMN1</i>. Mutations in <i>SMN</i> could affect several molecular processes, among which aberrant pre-mRNA splicing caused by defective snRNP biogenesis is hypothesized as a major cause of SMA. To date little is known about the interactions of <i>SMN</i> with other splicing factor genes and how SMN affects splicing <i>in vivo</i>. The nematode <i>Caenorhabditis elegans</i> carries a single ortholog of <i>SMN</i>, <i>smn-1</i>, and has been used as a model for studying the molecular functions of SMN. We analyzed RNA splicing of reporter genes in an <i>smn-1</i> deletion mutant and found that <i>smn-1</i> is required for efficient splicing at weak 3′ splice sites. Genetic studies indicate that the defective lifespan and motor functions of the <i>smn-1</i> deletion mutants could be significantly improved by mutations of the splicing factor U2AF large subunit gene <i>uaf-1</i>. In <i>smn-1</i> mutants we detected a reduced expression of U1 and U5 snRNAs and an increased expression of U2, U4 and U6 snRNAs. Our study verifies an essential role of <i>smn-1</i> for RNA splicing <i>in vivo</i>, identifies the <i>uaf-1</i> gene as a potential genetic modifier of <i>smn-1</i> mutants, and suggests that SMN-1 has multifaceted effects on the expression of spliceosomal snRNAs.