title: Developmental arrest of Drosophila survival motor neuron (Smn) mutants accounts for differences in expression of minor intron-containing genes.
abstract: Reduced levels of survival motor neuron (SMN) protein lead to a neuromuscular disease called spinal muscular atrophy (SMA). Animal models of SMA recapitulate many aspects of the human disease, including locomotion and viability defects, but have thus far failed to uncover the causative link between a lack of SMN protein and neuromuscular dysfunction. While SMN is known to assemble small nuclear ribonucleoproteins (snRNPs) that catalyze pre-mRNA splicing, it remains unclear whether disruptions in splicing are etiologic for SMA. To investigate this issue, we carried out RNA deep-sequencing (RNA-seq) on age-matched Drosophila Smn-null and wild-type larvae. Comparison of genome-wide mRNA expression profiles with publicly available data sets revealed the timing of a developmental arrest in the Smn mutants. Furthermore, genome-wide differences in splicing between wild-type and Smn animals did not correlate with changes in mRNA levels. Specifically, we found that mRNA levels of genes that contain minor introns vary more over developmental time than they do between wild-type and Smn mutants. An analysis of reads mapping to minor-class intron-exon junctions revealed only small changes in the splicing of minor introns in Smn larvae, within the normal fluctuations that occur throughout development. In contrast, Smn mutants displayed a prominent increase in levels of stress-responsive transcripts, indicating a systemic response to the developmental arrest induced by loss of SMN protein. These findings not only provide important mechanistic insight into the developmental arrest displayed by Smn mutants, but also argue against a minor-intron-dependent etiology for SMA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Garcia
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Lu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Meers
authors.forename: Kavita
authors.initials: K
authors.lastname: Praveen
authors.forename: A Gregory
authors.initials: AG
authors.lastname: Matera
mesh_terms: D000818:Animals; D001483:Base Sequence; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development; D020869:Gene Expression Profiling; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007814:Larva / Q000235:genetics; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics*; D017411:Ribonucleoproteins, Small Nuclear / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA
chemical_list: D029721:Drosophila Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012322:RNA Precursors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D017411:Ribonucleoproteins, Small Nuclear; C542563:Smn protein, Drosophila; C572149:insulin-like peptide 8, Drosophila
keywords: Drosophila insulin-like peptide 8; RNA-sequencing; dILP8; minor intron; snRNP; spinal muscular atrophy; splicing; stress signaling pathways; survival motor neuron; transcriptome