A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2
| Autor: | Dominik M. Duelli, Michelle L. Hastings, Francine M. Jodelka, Allison D. Ebert |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
animal diseases
RNA Splicing SMN1 Biology Ribonucleoprotein U1 Small Nuclear Muscular Atrophy Spinal 03 medical and health sciences Exon Mice 0302 clinical medicine RNA Small Nuclear Genetics medicine Animals Humans snRNP Molecular Biology Genetics (clinical) 030304 developmental biology Feedback Physiological 0303 health sciences Binding Sites Alternative splicing Survival of motor neuron General Medicine Spinal muscular atrophy Articles Exons medicine.disease Cell biology nervous system diseases Survival of Motor Neuron 2 Protein HEK293 Cells nervous system RNA splicing 030217 neurology & neurosurgery Small nuclear RNA HeLa Cells |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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