title: A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2.
abstract: Spinal muscular atrophy (SMA) is a neurological disorder characterized by motor neuron degeneration and progressive muscle paralysis. The disease is caused by a reduction in survival of motor neuron (SMN) protein resulting from homozygous deletion of the SMN1 gene. SMN protein is also encoded by SMN2. However, splicing of SMN2 exon 7 is defective, and consequently, the majority of the transcripts produce a truncated, unstable protein. SMN protein itself has a role in splicing. The protein is required for the biogenesis of spliceosomal snRNPs, which are essential components of the splicing reaction. We now show that SMN protein abundance affects the splicing of SMN2 exon 7, revealing a feedback loop inSMN expression. The reduced SMN protein concentration observed in SMA samples and in cells depleted of SMN correlates with a decrease in cellular snRNA levels and a decrease in SMN2 exon 7 splicing. Furthermore, altering the relative abundance or activity of individual snRNPs has distinct effects on exon 7 splicing, demonstrating that core spliceosomal snRNPs influence SMN2 alternative splicing. Our results identify a feedback loop in SMN expression by which low SMN protein levels exacerbate SMN exon 7 skipping, leading to a further reduction in SMN protein. These results imply that a modest increase in SMN protein abundance may cause a disproportionately large increase in SMN expression, a finding that is important for assessing the therapeutic potential of SMA treatments and understanding disease pathogenesis.
authors.affiliation: Department of Cell Biology and Anatomy, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
authors.forename: Francine M
authors.initials: FM
authors.lastname: Jodelka
authors.forename: Allison D
authors.initials: AD
authors.lastname: Ebert
authors.forename: Dominik M
authors.initials: DM
authors.lastname: Duelli
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Hastings
mesh_terms: D000818:Animals; D001665:Binding Sites; D005091:Exons / Q000235:genetics; D025461:Feedback, Physiological; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D012342:RNA, Small Nuclear / Q000378:metabolism; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
chemical_list: D012342:RNA, Small Nuclear; D017412:Ribonucleoprotein, U1 Small Nuclear; C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein