title: A global regulatory mechanism for activating an exon network required for neurogenesis.
abstract: The vertebrate and neural-specific Ser/Arg (SR)-related protein nSR100/SRRM4 regulates an extensive program of alternative splicing with critical roles in nervous system development. However, the mechanism by which nSR100 controls its target exons is poorly understood. We demonstrate that nSR100-dependent neural exons are associated with a unique configuration of intronic cis-elements that promote rapid switch-like regulation during neurogenesis. A key feature of this configuration is the insertion of specialized intronic enhancers between polypyrimidine tracts and acceptor sites that bind nSR100 to potently activate exon inclusion in neural cells while weakening 3' splice site recognition and contributing to exon skipping in nonneural cells. nSR100 further operates by forming multiple interactions with early spliceosome components bound proximal to 3' splice sites. These multifaceted interactions achieve dominance over neural exon silencing mediated by the splicing regulator PTBP1. The results thus illuminate a widespread mechanism by which a critical neural exon network is activated during neurogenesis.
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Bushra
authors.initials: B
authors.lastname: Raj
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Manuel
authors.initials: M
authors.lastname: Irimia
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Braunschweig
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Timothy
authors.initials: T
authors.lastname: Sterne-Weiler
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Dave
authors.initials: D
authors.lastname: O'Hanlon
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
authors.forename: Zhen-Yuan
authors.initials: ZY
authors.lastname: Lin
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
authors.forename: Ginny I
authors.initials: GI
authors.lastname: Chen
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Easton
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Jernej
authors.initials: J
authors.lastname: Ule
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.affiliation: Computational Genomics Group, Universitat Pompeu Fabra, Doctor Aiguader 88, 08003 Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Eyras
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: b.blencowe@utoronto.ca.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D005091:Exons; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D055495:Neurogenesis / Q000235:genetics*; D059372:Nucleotide Motifs
chemical_list: D009419:Nerve Tissue Proteins; C543899:nSR100 protein, mouse