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

  1. Yuhki Saito
  2. Soledad Miranda-Rottmann
  3. Matteo Ruggiu
  4. Christopher Y Park
  5. John J Fak
  6. Ru Zhong
  7. Jeremy S Duncan
  8. Brian A Fabella
  9. Harald J Junge
  10. Zhe Chen
  11. Roberto Araya
  12. Bernd Fritzsch
  13. A J Hudspeth
  14. Robert B Darnell  Is a corresponding author
  1. Howard Hughes Medical Institute, The Rockefeller University, United States
  2. New York Genome Center, United States
  3. University of Iowa, United States
  4. University of Colorado, Boulder, United States
  5. University of Montreal, Canada

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.

Article and author information

Author details

  1. Yuhki Saito

    Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Soledad Miranda-Rottmann

    Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Matteo Ruggiu

    Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Christopher Y Park

    New York Genome Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. John J Fak

    Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ru Zhong

    Laboratory of Molecular Neuro-oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jeremy S Duncan

    Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Brian A Fabella

    Laboratory of Sensory Neuroscience, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Harald J Junge

    Department of MCDB, University of Colorado, Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Zhe Chen

    Department of MCDB, University of Colorado, Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Roberto Araya

    Department of Neurosciences, Faculty of Medicine, University of Montreal, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  12. Bernd Fritzsch

    Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. A J Hudspeth

    Laboratory of Sensory Neuroscience, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Robert B Darnell

    Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, United States
    For correspondence
    darnelr@rockefeller.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Huda Y Zoghbi, Baylor College of Medicine, United States

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.

Version history

  1. Received: January 12, 2016
  2. Accepted: May 23, 2016
  3. Accepted Manuscript published: May 25, 2016 (version 1)
  4. Version of Record published: July 1, 2016 (version 2)

Copyright

© 2016, Saito et al.

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.

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  1. Yuhki Saito
  2. Soledad Miranda-Rottmann
  3. Matteo Ruggiu
  4. Christopher Y Park
  5. John J Fak
  6. Ru Zhong
  7. Jeremy S Duncan
  8. Brian A Fabella
  9. Harald J Junge
  10. Zhe Chen
  11. Roberto Araya
  12. Bernd Fritzsch
  13. A J Hudspeth
  14. Robert B Darnell
(2016)
NOVA2-mediated RNA regulation is required for axonal pathfinding during development
eLife 5:e14371.
https://doi.org/10.7554/eLife.14371

Share this article

https://doi.org/10.7554/eLife.14371

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