title: A pair of RNA-binding proteins controls networks of splicing events contributing to specialization of neural cell types.
abstract: Alternative splicing is important for the development and function of the nervous system, but little is known about the differences in alternative splicing between distinct types of neurons. Furthermore, the factors that control cell-type-specific splicing and the physiological roles of these alternative isoforms are unclear. By monitoring alternative splicing at single-cell resolution in Caenorhabditis elegans, we demonstrate that splicing patterns in different neurons are often distinct and highly regulated. We identify two conserved RNA-binding proteins, UNC-75/CELF and EXC-7/Hu/ELAV, which regulate overlapping networks of splicing events in GABAergic and cholinergic neurons. We use the UNC-75 exon network to discover regulators of synaptic transmission and to identify unique roles for isoforms of UNC-64/Syntaxin, a protein required for synaptic vesicle fusion. Our results indicate that combinatorial regulation of alternative splicing in distinct neurons provides a mechanism to specialize metazoan nervous systems.
authors.affiliation: FAS Center for Systems Biology, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Norris
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
authors.forename: Shangbang
authors.initials: S
authors.lastname: Gao
authors.affiliation: FAS Center for Systems Biology, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Norris
authors.affiliation: Donnelly Centre for Cellular and Biomolecular Research, 160 College Street, Toronto, ON M5S 3E1, Canada.
authors.forename: Debashish
authors.initials: D
authors.lastname: Ray
authors.affiliation: Donnelly Centre for Cellular and Biomolecular Research, 160 College Street, Toronto, ON M5S 3E1, Canada.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ramani
authors.affiliation: Donnelly Centre for Cellular and Biomolecular Research, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Fraser
authors.affiliation: Donnelly Centre for Cellular and Biomolecular Research, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Quaid
authors.initials: Q
authors.lastname: Morris
authors.affiliation: Donnelly Centre for Cellular and Biomolecular Research, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hughes
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, 600 University Avenue, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. Electronic address: zhen@lunenfeld.ca.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhen
authors.affiliation: FAS Center for Systems Biology, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA. Electronic address: jcalarco@fas.harvard.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Calarco
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000502:physiology*; D059329:Cholinergic Neurons / Q000166:cytology* / Q000378:metabolism; D059330:GABAergic Neurons / Q000166:cytology* / Q000378:metabolism; D009154:Mutation; D009420:Nervous System / Q000196:embryology / Q000254:growth & development; D020033:Protein Isoforms / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D009435:Synaptic Transmission / Q000235:genetics* / Q000502:physiology; D013572:Synaptic Vesicles / Q000378:metabolism; D050827:Syntaxin 1 / Q000235:genetics*
chemical_list: D029742:Caenorhabditis elegans Proteins; C473926:EXC-7 protein, C elegans; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D050827:Syntaxin 1; C581735:UNC-75 protein, C elegans; C494215:unc-64 protein, C elegans