SAM68 is a physiological regulator of SMN2 splicing in spinal muscular atrophy

Vittoria Pagliarini, Laura Pelosi, Maria Blaire Bustamante, Annalisa Nobili, Maria Grazia Berardinelli, Marcello D'Amelio, Antonio Musarò, Claudio Sette

Research output: Contribution to journalArticlepeer-review

Abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by loss of motor neurons in patients with null mutations in the SMN1 gene. The almost identical SMN2 gene is unable to compensate for this deficiency because of the skipping of exon 7 during pre-messenger RNA (mRNA) processing. Although several splicing factors can modulate SMN2 splicing in vitro, the physiological regulators of this disease-causing event are unknown. We found that knockout of the splicing factor SAM68 partially rescued body weight and viability of SMA?7 mice. Ablation of SAM68 function promoted SMN2 splicing and expression in SMA?7 mice, correlating with amelioration of SMA-related defects in motor neurons and skeletal muscles. Mechanistically, SAM68 binds to SMN2 pre-mRNA, favoring recruitment of the splicing repressor hnRNP A1 and interfering with that of U2AF65 at the 3' splice site of exon 7. These findings identify SAM68 as the first physiological regulator of SMN2 splicing in an SMA mouse model.

Original languageEnglish
Pages (from-to)77-90
Number of pages14
JournalJournal of Cell Biology
Volume211
Issue number1
DOIs
Publication statusPublished - Oct 12 2015

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'SAM68 is a physiological regulator of SMN2 splicing in spinal muscular atrophy'. Together they form a unique fingerprint.

Cite this