title: NOVA2-mediated RNA regulation is required for axonal pathfinding during development.
abstract: The neuron specific RNA-binding proteins NOVA1 and NOVA2 are highly homologous alternative splicing regulators. NOVA proteins regulate at least 700 alternative splicing events in vivo, yet relatively little is known about the biologic consequences of NOVA action and in particular about functional differences between NOVA1 and NOVA2. Transcriptome-wide searches for isoform-specific functions, using NOVA1 and NOVA2 specific HITS-CLIP and RNA-seq data from mouse cortex lacking either NOVA isoform, reveals that NOVA2 uniquely regulates alternative splicing events of a series of axon guidance related genes during cortical development. Corresponding axonal pathfinding defects were specific to NOVA2 deficiency: Nova2-/- but not Nova1-/- mice had agenesis of the corpus callosum, and axonal outgrowth defects specific to ventral motoneuron axons and efferent innervation of the cochlea. Thus we have discovered that NOVA2 uniquely regulates alternative splicing of a coordinate set of transcripts encoding key components in cortical, brainstem and spinal axon guidance/outgrowth pathways during neural differentiation, with severe functional consequences in vivo.
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Yuhki
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Soledad
authors.initials: S
authors.lastname: Miranda-Rottmann
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Matteo
authors.initials: M
authors.lastname: Ruggiu
authors.affiliation: New York Genome Center, New York, United States.
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Park
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Fak
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Ru
authors.initials: R
authors.lastname: Zhong
authors.affiliation: Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, United States.
authors.forename: Jeremy S
authors.identifier: 0000-0002-5555-3273
authors.initials: JS
authors.lastname: Duncan
authors.affiliation: Laboratory of Sensory Neuroscience, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Fabella
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Boulder, United States.
authors.forename: Harald J
authors.initials: HJ
authors.lastname: Junge
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Boulder, United States.
authors.forename: Zhe
authors.identifier: 0000-0003-0683-9491
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Neurosciences, Faculty of Medicine, University of Montreal, Montreal, Canada.
authors.forename: Roberto
authors.initials: R
authors.lastname: Araya
authors.affiliation: Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, United States.
authors.forename: Bernd
authors.initials: B
authors.lastname: Fritzsch
authors.affiliation: Laboratory of Sensory Neuroscience, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.
authors.forename: A J
authors.identifier: 0000-0002-0295-1323
authors.initials: AJ
authors.lastname: Hudspeth
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States.|New York Genome Center, New York, United States.
authors.forename: Robert B
authors.identifier: 0000-0002-5134-8088
authors.initials: RB
authors.lastname: Darnell
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000071437:Axon Guidance; D002540:Cerebral Cortex / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D000090682:Neuro-Oncological Ventral Antigen; D009474:Neurons / Q000502:physiology*; D012313:RNA / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D000090682:Neuro-Oncological Ventral Antigen; C515624:Nova2 protein, mouse; D016601:RNA-Binding Proteins; D012313:RNA
keywords: HITS-CLIP; NOVA; RNA-seq; agenesis corpus callosum; axon guidance; cochlear neuron; motoneuron; mouse; neuroscience; splicing