Pagliarini Vittoria, Pelosi Laura, Bustamante Maria Blaire, Nobili Annalisa, Berardinelli Maria Grazia, D'Amelio Marcello, Musarò Antonio, Sette Claudio
Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy.
Institute Pasteur Cenci-Bolognetti Foundation, DAHFMO-Unit of Histology and Medical Embryology, IIM, University of Rome La Sapienza, 00161 Rome, Italy.
J Cell Biol. 2015 Oct 12;211(1):77-90. doi: 10.1083/jcb.201502059. Epub 2015 Oct 5.
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.
脊髓性肌萎缩症（SMA）是一种神经退行性疾病，由SMN1基因发生无效突变的患者体内运动神经元丧失所致。几乎相同的SMN2基因由于在前体信使RNA（mRNA）加工过程中外显子7的跳跃而无法弥补这一缺陷。尽管几种剪接因子在体外可调节SMN2剪接，但导致该疾病的这一事件的生理调节因子尚不清楚。我们发现敲除剪接因子SAM68可部分挽救SMAΔ7小鼠的体重和存活率。SAM68功能的缺失促进了SMAΔ7小鼠中SMN2的剪接和表达，这与运动神经元和骨骼肌中SMA相关缺陷的改善相关。从机制上讲，SAM68与SMN2前体mRNA结合，有利于剪接抑制因子hnRNP A1的募集，并在第7外显子的3'剪接位点干扰U2AF65的募集。这些发现确定SAM68是SMA小鼠模型中SMN2剪接的首个生理调节因子。
