RT Journal Article SR Electronic T1 Transcriptomic comparison of Drosophila snRNP biogenesis mutants: implications for Spinal Muscular Atrophy JF bioRxiv FD Cold Spring Harbor Laboratory SP 044693 DO 10.1101/044693 A1 Eric L. Garcia A1 Ying Wen A1 Kavita Praveen A1 A. Gregory Matera YR 2016 UL http://biorxiv.org/content/early/2016/03/25/044693.abstract AB Spinal Muscular Atrophy (SMA) is caused by deletion or mutation of the Survival Motor Neuron 1 gene (SMN1)1, but the mechanism whereby reduced levels of SMN protein lead to disease is unknown. SMN functions in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) and potential splicing defects have been uncovered in various animal models of SMA. We used disruptions in Smn and two additional snRNP biogenesis genes, Phax and Ars2, to classify RNA processing differences as snRNP-dependent or Smn gene specific in Drosophila. Although more numerous, the processing changes in Ars2 mutants were generally distinct from those identified in Phax and Smn animals. Phax and Smn null mutants exhibited comparable reductions in steady-state snRNA levels, and direct comparison of their transcriptomes uncovered a shared set of alternative splicing changes. Transgenic expression of Phax and Smn in the respective mutant backgrounds significantly rescued both snRNA levels as well as alternative splicing. When compared to the Smn wild-type rescue line, three additional disease models (bearing SMA-causing point mutations in Smn) displayed only small-to-indistinguishable differences in snRNA levels and the identified splicing disruptions. Comparison of these intermediate SMA models revealed fewer than 10% shared splicing differences. Instead, the three Smn point mutants displayed common increases in stress responsive transcripts that correlated with phenotypic severity. These findings uncouple organismal viability defects from the general housekeeping function of SMN and suggest that SMN-specific changes in gene expression may be important for understanding how loss of SMN ultimately causes disease.