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 SMAΔ7 mice. Ablation of SAM68 function promoted SMN2 splicing and expression in SMAΔ7 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.

Pagliarini, V., Pelosi, L., Bustamante, M., Nobili, A., Berardinelli, M., D'Amelio, M., et al. (2015). SAM68 is a physiological regulator of SMN2 splicing in spinal muscular atrophy. THE JOURNAL OF CELL BIOLOGY, 211(1), 77-90 [10.1083/jcb.201502059].

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

SETTE, CLAUDIO
2015-10-12

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 SMAΔ7 mice. Ablation of SAM68 function promoted SMN2 splicing and expression in SMAΔ7 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.
12-ott-2015
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/16 - ANATOMIA UMANA
English
Pagliarini, V., Pelosi, L., Bustamante, M., Nobili, A., Berardinelli, M., D'Amelio, M., et al. (2015). SAM68 is a physiological regulator of SMN2 splicing in spinal muscular atrophy. THE JOURNAL OF CELL BIOLOGY, 211(1), 77-90 [10.1083/jcb.201502059].
Pagliarini, V; Pelosi, L; Bustamante, M; Nobili, A; Berardinelli, M; D'Amelio, M; Musarò, A; Sette, C
Articolo su rivista
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/131695
Citazioni
  • ???jsp.display-item.citation.pmc??? 15
  • Scopus 24
  • ???jsp.display-item.citation.isi??? 23
social impact