A Drosophila Model of Spinal Muscular Atrophy Uncouples snRNP Biogenesis Functions of Survival Motor Neuron from Locomotion and Viability Defects

Abstract

Summary The Spinal Muscular Atrophy (SMA) protein, survival motor neuron (SMN), functions in the biogenesis of small nuclear ribonucleoproteins (snRNPs). SMN has also been implicated in tissue-specific functions, however, it remains unclear which of these is important for the etiology of SMA. Smn null mutants are larval lethals and show significant locomotion defects as well as reductions in minor-class spliceosomal snRNAs. Despite these reductions, we found no appreciable defects in splicing of mRNAs containing minor-class introns. Transgenic expression of low levels of either wild-type or an SMA patient-derived form of SMN rescued the larval lethality and locomotor defects, however, snRNA levels were not restored. Thus, the snRNP biogenesis function of SMN is not a major contributor to the phenotype of Smn null mutants. These findings have major implications for SMA etiology because they show that SMN's role in snRNP biogenesis can be uncoupled from the organismal viability and locomotor defects.

Developmental arrest of Drosophila survival motor neuron (Smn) mutants accounts for differences in expression of minor intron-containing genes

“…Thus, a tractable hypothesis posits the existence of a neuromuscular-specific minor-intron splicing event that is highly sensitive to disruptions in snRNP assembly. Testing this hypothesis in Drosophila models of SMA, two recent reports dispute the extent to which defects in minor intron splicing may account for SMA-like phenotypes Praveen et al 2012). First, we showed that transgenic expression of low levels of wild-type dSMN protein could fully rescue larval motility and viability without fully rescuing snRNA levels (Praveen et al 2012).…”

“…First, we showed that transgenic expression of low levels of wild-type dSMN protein could fully rescue larval motility and viability without fully rescuing snRNA levels (Praveen et al 2012). Second, Smn-null animals showed modest (30%-50%) decreases in the levels of four minor intron-containing transcripts; however, the levels of these four mRNAs did not correlate with expression of the wild-type Smn rescue construct (Praveen et al 2012). This study provides strong evidence uncoupling the snRNP assembly functions of dSMN from the organismal motility and viability defects.…”

“…Testing this hypothesis in Drosophila models of SMA, two recent reports dispute the extent to which defects in minor intron splicing may account for SMA-like phenotypes Praveen et al 2012). First, we showed that transgenic expression of low levels of wild-type dSMN protein could fully rescue larval motility and viability without fully rescuing snRNA levels (Praveen et al 2012). Second, Smn-null animals showed modest (30%-50%) decreases in the levels of four minor intron-containing transcripts; however, the levels of these four mRNAs did not correlate with expression of the wild-type Smn rescue construct (Praveen et al 2012).…”

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

“…Presymptomatic SMA mice exhibit motor neuronspecific skipping of the agrin Z exons, which are involved in postsynaptic organization of acetylcholine receptors at the neuromuscular junction and may contribute to the NMJ defects seen in human patients (20). Other models have suggested that locomotor defects arising from SMN loss are independent of defective snRNP biogenesis, and that developmental delays in SMN-deficient animals are responsible for such apparent splicing differences (21,22).…”

Spinal Muscular Atrophy: Journeying From Bench to Bedside

“…It is thought that by complexing with such RNPs, SMN regulates the transport of the various transcripts into the axons and terminals of motor neurons in response to local or developmental cues. This motor neuron-centric view of the role of SMN in SMA has gained additional traction, albeit indirectly, from studies claiming not only to have uncoupled motor neuron dysfunction from snRNP biogenesis [53], but also to have provided a plausible explanation for the alleged disruption of the minor spliceosome in fly models of the disease [54]. The contrasting views of the critical role for the SMN protein in explaining the SMA phenotype clearly argue for additional careful work, and it is not unlikely that multiple pathways, including one in which low protein disrupts histone mRNA processing [55], all contribute, in varying measures, to the overall disease.…”