1. Developmental Biology
  2. Neuroscience

NOVA regulate Dcc alternative splicing during neuronal migration and axon guidance in the spinal cord

  1. Janelle C Leggere
  2. Yuhki Saito
  3. Robert B Darnell
  4. Marc Tessier-Lavigne
  5. Harald J Junge
  6. Zhe Chen  Is a corresponding author
  1. University of Colorado, Boulder, United States
  2. Howard Hughes Medical Institute, The Rockefeller University, United States
  3. The Rockefeller University, United States
https://doi.org/10.7554/eLife.14264
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  1. Janelle C Leggere
  2. Yuhki Saito
  3. Robert B Darnell
  4. Marc Tessier-Lavigne
  5. Harald J Junge
  6. Zhe Chen
(2016)
NOVA regulate Dcc alternative splicing during neuronal migration and axon guidance in the spinal cord
eLife 5:e14264.
https://doi.org/10.7554/eLife.14264
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Abstract

RNA-binding proteins (RBPs) control multiple aspects of post-transcriptional gene regulation and function during various biological processes in the nervous system. To further reveal the functional significance of RBPs during neural development, we carried out an in vivo RNAi screen in the dorsal spinal cord interneurons, including the commissural neurons. We found that the NOVA family of RBPs play a key role in neuronal migration, axon outgrowth, and axon guidance. Interestingly, Nova mutants display similar defects as the knockout of the Dcc transmembrane receptor. We show here that Nova deficiency disrupts the alternative splicing of Dcc, and that restoring Dcc splicing in Nova knockouts is able to rescue the defects. Together, our results demonstrate that the production of DCC splice variants controlled by NOVA has a crucial function during many stages of commissural neuron development.

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Author details

  1. Janelle C Leggere

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

  2. 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.

  3. Robert B Darnell

    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. Marc Tessier-Lavigne

    Laboratory of Brain Development and Repair, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Harald J Junge

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

  6. Zhe Chen

    Department of MCDB, University of Colorado, Boulder, Boulder, United States
    For correspondence
    zhe.chen@colorado.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to the approved institutional animal care and use committee (IACUC) protocol (#1310.02) of the University of Colorado at Boulder.

Copyright

© 2016, Leggere 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. Janelle C Leggere
  2. Yuhki Saito
  3. Robert B Darnell
  4. Marc Tessier-Lavigne
  5. Harald J Junge
  6. Zhe Chen
(2016)
NOVA regulate Dcc alternative splicing during neuronal migration and axon guidance in the spinal cord
eLife 5:e14264.
https://doi.org/10.7554/eLife.14264

Share this article

https://doi.org/10.7554/eLife.14264

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Further reading

    1. Neuroscience

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

    Yuhki Saito, Soledad Miranda-Rottmann ... Robert B Darnell
    Research Article Updated

    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.