1. Neuroscience
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CELF RNA binding proteins promote axon regeneration in C. elegans and mammals through alternative splicing of Syntaxins

  1. Lizhen Chen
  2. Zhijie Liu
  3. Bing Zhou
  4. Chaoliang Wei
  5. Yu Zhou
  6. Michael G Rosenfeld
  7. Xiang-Dong Fu
  8. Andrew D Chisholm
  9. Yishi Jin  Is a corresponding author
  1. University of Texas Health Science Center at San Antonio, United States
  2. University of California, San Diego, United States
  3. Howard Hughes Medical Institute, University of California, San Diego, United States
Research Article
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Cite this article as: eLife 2016;5:e16072 doi: 10.7554/eLife.16072
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Abstract

Axon injury triggers dramatic changes in gene expression. While transcriptional regulation of injury-induced gene expression is widely studied, less is known about the roles of RNA binding proteins (RBPs) in post-transcriptional regulation during axon regeneration. In C. elegans the CELF (CUGBP and Etr-3 Like Factor) family RBP UNC-75 is required for axon regeneration. Using crosslinking immunoprecipitation coupled with deep sequencing (CLIP-seq) we identify a set of genes involved in synaptic transmission as mRNA targets of UNC-75. In particular, we show that UNC-75 regulates alternative splicing of two mRNA isoforms of the SNARE Syntaxin/unc-64. In C. elegans mutants lacking unc-75 or its targets, regenerating axons form growth cones, yet are deficient in extension. Extending these findings to mammalian axon regeneration, we show that mouse Celf2 expression is upregulated after peripheral nerve injury and that Celf2 mutant mice are defective in axon regeneration. Further, mRNAs for several Syntaxins show CELF2 dependent regulation. Our data delineate a post-transcriptional regulatory pathway with a conserved role in regenerative axon extension.

Article and author information

Author details

  1. Lizhen Chen

    Barshop Institute for Longevity and Aging Studies, Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Zhijie Liu

    Department of Medicine, School of Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Bing Zhou

    Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Chaoliang Wei

    Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yu Zhou

    Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Michael G Rosenfeld

    Howard Hughes Medical Institute, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Xiang-Dong Fu

    Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Andrew D Chisholm

    Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Yishi Jin

    Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, San Diego, United States
    For correspondence
    yijin@ucsd.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 approved institutional animal care and use committee (IACUC) protocols (S13072) of the University of California. All surgery was performed under anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Graeme W Davis, University of California, San Francisco, United States

Publication history

  1. Received: March 15, 2016
  2. Accepted: June 1, 2016
  3. Accepted Manuscript published: June 2, 2016 (version 1)
  4. Version of Record published: July 15, 2016 (version 2)

Copyright

© 2016, Chen 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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