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

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.

Article and author information

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.

Metrics

  • 3,556
    views
  • 662
    downloads
  • 52
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Developmental Biology
    2. Genetics and Genomics
    Ignacy Czajewski, Bijayalaxmi Swain ... Daan MF van Aalten
    Research Article

    O-GlcNAcylation is an essential intracellular protein modification mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Recently, missense mutations in OGT have been linked to intellectual disability, indicating that this modification is important for the development and functioning of the nervous system. However, the processes that are most sensitive to perturbations in O-GlcNAcylation remain to be identified. Here, we uncover quantifiable phenotypes in the fruit fly Drosophila melanogaster carrying a patient-derived OGT mutation in the catalytic domain. Hypo-O-GlcNAcylation leads to defects in synaptogenesis and reduced sleep stability. Both these phenotypes can be partially rescued by genetically or chemically targeting OGA, suggesting that a balance of OGT/OGA activity is required for normal neuronal development and function.

    1. Developmental Biology
    Martina Jabloñski, Guillermina M Luque ... Mariano G Buffone
    Research Article

    Mammalian sperm delve into the female reproductive tract to fertilize the female gamete. The available information about how sperm regulate their motility during the final journey to the fertilization site is extremely limited. In this work, we investigated the structural and functional changes in the sperm flagellum after acrosomal exocytosis (AE) and during the interaction with the eggs. The evidence demonstrates that the double helix actin network surrounding the mitochondrial sheath of the midpiece undergoes structural changes prior to the motility cessation. This structural modification is accompanied by a decrease in diameter of the midpiece and is driven by intracellular calcium changes that occur concomitant with a reorganization of the actin helicoidal cortex. Midpiece contraction occurs in a subset of cells that undergo AE, and live-cell imaging during in vitro fertilization showed that the midpiece contraction is required for motility cessation after fusion is initiated. These findings provide the first evidence of the F-actin network’s role in regulating sperm motility, adapting its function to meet specific cellular requirements during fertilization, and highlighting the broader significance of understanding sperm motility.