title: Distal Alternative Last Exons Localize mRNAs to Neural Projections.
abstract: Spatial restriction of mRNA to distinct subcellular locations enables local regulation and synthesis of proteins. However, the organizing principles of mRNA localization remain poorly understood. Here we analyzed subcellular transcriptomes of neural projections and soma of primary mouse cortical neurons and two neuronal cell lines and found that alternative last exons (ALEs) often confer isoform-specific localization. Surprisingly, gene-distal ALE isoforms were four times more often localized to neurites than gene-proximal isoforms. Localized isoforms were induced during neuronal differentiation and enriched for motifs associated with muscleblind-like (Mbnl) family RNA-binding proteins. Depletion of Mbnl1 and/or Mbnl2 reduced localization of hundreds of transcripts, implicating Mbnls in localization of mRNAs to neurites. We provide evidence supporting a model in which the linkage between genomic position of ALEs and subcellular localization enables coordinated induction of localization-competent mRNA isoforms through a post-transcriptional regulatory program that is induced during differentiation and reversed in cellular reprogramming and cancer.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: J Matthew
authors.initials: JM
authors.lastname: Taliaferro
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Vidaki
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Ruan
authors.initials: R
authors.lastname: Oliveira
authors.affiliation: Department of Genetics and Genome Sciences, Institute for Systems Genomics, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Olson
authors.affiliation: Department of Genetics and Genome Sciences, Institute for Systems Genomics, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhan
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Tanvi
authors.initials: T
authors.lastname: Saxena
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Wang
authors.affiliation: Department of Genetics and Genome Sciences, Institute for Systems Genomics, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Brenton R
authors.initials: BR
authors.lastname: Graveley
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Gertler
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Maurice S
authors.initials: MS
authors.lastname: Swanson
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: cburge@mit.edu.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Burge
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D005091:Exons; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D016501:Neurites / Q000378:metabolism*; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C479922:Mbnl1 protein, mouse; C529512:Mbnl2 protein, mouse; D020033:Protein Isoforms; D012333:RNA, Messenger; D016601:RNA-Binding Proteins