TY - JOUR T1 - Transcriptomic comparison of <em>Drosophila</em> snRNP biogenesis mutants: implications for Spinal Muscular Atrophy JF - bioRxiv DO - 10.1101/044693 SP - 044693 AU - Eric L. Garcia AU - Ying Wen AU - Kavita Praveen AU - A. Gregory Matera Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/03/25/044693.abstract N2 - 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. ER -