NOVA2-mediated RNA regulation is required for axonal pathfinding during development

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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.

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Yuhki Saito

Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States

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The authors declare that no competing interests exist.
Soledad Miranda-Rottmann

Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States

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Matteo Ruggiu

Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States

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Christopher Y Park

New York Genome Center, New York, United States

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John J Fak

Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States

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Ru Zhong

Laboratory of Molecular Neuro-oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States

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Jeremy S Duncan

Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, United States

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Brian A Fabella

Laboratory of Sensory Neuroscience, Howard Hughes Medical Institute, The Rockefeller University, New York, United States

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Harald J Junge

Department of MCDB, University of Colorado, Boulder, Boulder, United States

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Zhe Chen

Department of MCDB, University of Colorado, Boulder, Boulder, United States

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Roberto Araya

Department of Neurosciences, Faculty of Medicine, University of Montreal, Montreal, Canada

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Bernd Fritzsch

Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, United States

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A J Hudspeth

Laboratory of Sensory Neuroscience, Howard Hughes Medical Institute, The Rockefeller University, New York, United States

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Robert B Darnell

Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States

For correspondence
darnelr@rockefeller.edu

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The authors declare that no competing interests exist.

Ethics

Animal experimentation: This studies were performed in compliance with protocols (#14678 and #07069) approved by the Institutional Animal Care and Use Committee (IACUC) of the Rockefeller University or with protocols (13-185 and 15-002) approved by the Comité de déontologie de l'expérimentation sur les animaux (CDEA) of the Univeristy of Montreal.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.