title: SMN is essential for the biogenesis of U7 small nuclear ribonucleoprotein and 3'-end formation of histone mRNAs.
abstract: Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a deficiency in the survival motor neuron (SMN) protein. SMN mediates the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) and possibly other RNPs. Here, we investigated SMN requirement for the biogenesis and function of U7--an snRNP specialized in the 3'-end formation of replication-dependent histone mRNAs that normally are not polyadenylated. We show that SMN deficiency impairs U7 snRNP assembly and decreases U7 levels in mammalian cells. The SMN-dependent U7 reduction affects endonucleolytic cleavage of histone mRNAs leading to abnormal accumulation of 3'-extended and polyadenylated transcripts followed by downstream changes in histone gene expression. Importantly, SMN deficiency induces defects of histone mRNA 3'-end formation in both SMA mice and human patients. These findings demonstrate that SMN is essential for U7 biogenesis and histone mRNA processing in vivo and identify an additional RNA pathway disrupted in SMA.
authors: Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors: Sarah
authors: S
authors: Tisdale
authors: Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors: Francesco
authors: F
authors: Lotti
authors: Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors: Luciano
authors: L
authors: Saieva
authors: Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
authors: James P
authors: JP
authors: Van Meerbeke
authors: Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
authors: Thomas O
authors: TO
authors: Crawford
authors: Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
authors: Charlotte J
authors: CJ
authors: Sumner
authors: Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors: George Z
authors: GZ
authors: Mentis
authors: Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA. Electronic address: lp2284@columbia.edu.
authors: Livio
authors: L
authors: Pellizzoni
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D020885:Ribonucleoprotein, U7 Small Nuclear / Q000378:metabolism*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D006657:Histones; D012333:RNA, Messenger; D020885:Ribonucleoprotein, U7 Small Nuclear; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein