title: SAM68 is a physiological regulator of SMN2 splicing in spinal muscular atrophy.
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.
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Pagliarini
authors.affiliation: Institute Pasteur Cenci-Bolognetti Foundation, DAHFMO-Unit of Histology and Medical Embryology, IIM, University of Rome La Sapienza, 00161 Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Pelosi
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy.
authors.forename: Maria Blaire
authors.initials: MB
authors.lastname: Bustamante
authors.affiliation: Laboratory of Molecular Neuroscience, Fondazione Santa Lucia, 00143 Rome, Italy Medical School University Campus Bio-Medico, 00128 Rome, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Nobili
authors.affiliation: Institute Pasteur Cenci-Bolognetti Foundation, DAHFMO-Unit of Histology and Medical Embryology, IIM, University of Rome La Sapienza, 00161 Rome, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Berardinelli
authors.affiliation: Laboratory of Molecular Neuroscience, Fondazione Santa Lucia, 00143 Rome, Italy Medical School University Campus Bio-Medico, 00128 Rome, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: D'Amelio
authors.affiliation: Institute Pasteur Cenci-Bolognetti Foundation, DAHFMO-Unit of Histology and Medical Embryology, IIM, University of Rome La Sapienza, 00161 Rome, Italy Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161 Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Musarò
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy Laboratory of Neuroembryology, Fondazione Santa Lucia, 00143 Rome, Italy claudio.sette@uniroma2.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Sette
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D005260:Female; D057809:HEK293 Cells; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000502:physiology*; D013116:Spinal Cord / Q000473:pathology; D055540:Survival of Motor Neuron 2 Protein / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C513253:Khdrbs1 protein, mouse; D016601:RNA-Binding Proteins; C000597152:SMN2 protein, mouse; D055540:Survival of Motor Neuron 2 Protein