title: Altered mRNA Splicing in SMN-Depleted Motor Neuron-Like Cells.
abstract: Spinal muscular atrophy (SMA) is an intractable neurodegenerative disease afflicting 1 in 6-10,000 live births. One of the key functions of the SMN protein is regulation of spliceosome assembly. Reduced levels of the SMN protein that are observed in SMA have been shown to result in aberrant mRNA splicing. SMN-dependent mis-spliced transcripts in motor neurons may cause stresses that are particularly harmful and may serve as potential targets for the treatment of motor neuron disease or as biomarkers in the SMA patient population. We performed deep RNA sequencing using motor neuron-like NSC-34 cells to screen for SMN-dependent mRNA processing changes that occur following acute depletion of SMN. We identified SMN-dependent splicing changes, including an intron retention event that results in the production of a truncated Rit1 transcript. This intron-retained transcript is stable and is mis-spliced in spinal cord from symptomatic SMA mice. Constitutively active Rit1 ameliorated the neurite outgrowth defect in SMN depleted NSC-34 cells, while expression of the truncated protein product of the mis-spliced Rit1 transcript inhibited neurite extension. These results reveal new insights into the biological consequence of SMN-dependent splicing in motor neuron-like cells.
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Sara K
authors.initials: SK
authors.lastname: Custer
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Timra D
authors.initials: TD
authors.lastname: Gilson
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: A Gary
authors.initials: AG
authors.lastname: Todd
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Jacob W
authors.initials: JW
authors.lastname: Astroski
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Hai
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Elliot J
authors.identifier: http://orcid.org/0000-0002-8104-0703
authors.initials: EJ
authors.lastname: Androphy
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation; D007438:Introns; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics*; D059467:Transcriptome
chemical_list: D012333:RNA, Messenger; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein