title: Context-dependent modulation of Pol II CTD phosphatase SSUP-72 regulates alternative polyadenylation in neuronal development.
abstract: Alternative polyadenylation (APA) is widespread in neuronal development and activity-mediated neural plasticity. However, the underlying molecular mechanisms are largely unknown. We used systematic genetic studies and genome-wide surveys of the transcriptional landscape to identify a context-dependent regulatory pathway controlling APA in the Caenorhabditis elegans nervous system. Loss of function in ssup-72, a Ser5 phosphatase for the RNA polymerase II (Pol II) C-terminal domain (CTD), dampens transcription termination at a strong intronic polyadenylation site (PAS) in unc-44/ankyrin yet promotes termination at the weak intronic PAS of the MAP kinase dlk-1. A nuclear protein, SYDN-1, which regulates neuronal development, antagonizes the function of SSUP-72 and several nuclear polyadenylation factors. This regulatory pathway allows the production of a neuron-specific isoform of unc-44 and an inhibitory isoform of dlk-1. Dysregulation of the unc-44 and dlk-1 mRNA isoforms in sydn-1 mutants impairs neuronal development. Deleting the intronic PAS of unc-44 results in increased pre-mRNA processing of neuronal ankyrin and suppresses sydn-1 mutants. These results reveal a mechanism by which regulation of CTD phosphorylation controls coding region APA in the nervous system.
authors.affiliation: Neurobiology Section, Division of Biological Sciences, University of California at San Diego, La Jolla, California 92093, USA; Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Neurobiology Section, Division of Biological Sciences, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Yingchuan B
authors.initials: YB
authors.lastname: Qi
authors.affiliation: Life Sciences Institute, Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA;
authors.forename: Vishal
authors.initials: V
authors.lastname: Khivansara
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Hairi
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Sang Young
authors.initials: SY
authors.lastname: Chun
authors.affiliation: Life Sciences Institute, Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA;
authors.forename: John K
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
authors.affiliation: Neurobiology Section, Division of Biological Sciences, University of California at San Diego, La Jolla, California 92093, USA; Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California 92093, USA; Department of Cellular and Molecular Medicine, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA;
authors.forename: Yishi
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000235:genetics / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000201:enzymology; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D026723:Polyadenylation; D011485:Protein Binding
chemical_list: D017487:Ankyrins; D029742:Caenorhabditis elegans Proteins; C093514:unc-44 protein, C elegans; C498050:DLK-1 protein, C elegans; D020930:MAP Kinase Kinase Kinases; D010749:Phosphoprotein Phosphatases; C000605376:SSUP-72 phosphatase, C elegans
keywords: C. elegans; DLK-1/MAP kinase; SYDN-1; UNC-44/ankyrin; axon and synapse development; pre-mRNA 3′ end processing