RbFox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels

  1. Francesco Tomassoni-Ardori
  2. Gianluca Fulgenzi
  3. Jodi Becker
  4. Colleen Barrick
  5. Mary Ellen Palko
  6. Skyler Kuhn
  7. Vishal Koparde
  8. Maggie Cam
  9. Sudhirkumar Yanpallewar
  10. Shalini Oberdoerffer
  11. Lino Tessarollo  Is a corresponding author
  1. National Cancer Institute, United States
  2. National Cancer Institute, National Institutes of Health, United States

Abstract

Brain Derived Neurotrophic Factor (BDNF) is a potent modulator of brain synaptic plasticity. Signaling defects caused by dysregulation of its NTrk2 (TrkB) kinase (TrkB.FL) and truncated receptors (TrkB.T1) have been linked to the pathophysiology of several neurological and neurodegenerative disorders. We found that upregulation of Rbfox1, an RNA binding protein associated with intellectual disability, epilepsy and autism, increases selectively hippocampal TrkB.T1 isoform expression. Physiologically, increased Rbfox1 impairs BDNF-dependent LTP which can be rescued by genetically restoring TrkB.T1 levels. RNA-seq analysis of hippocampi with upregulation of Rbfox1 in conjunction with the specific increase of TrkB.T1 isoform expression also shows that the genes affected by Rbfox1 gain of function are surprisingly different from those influenced by Rbfox1 deletion. These findings not only identify TrkB as a major target of Rbfox1 pathophysiology but also suggest that gain or loss of function of Rbfox1 regulate different genetic landscapes.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Table 1 and 2.

The following previously published data sets were used

Article and author information

Author details

  1. Francesco Tomassoni-Ardori

    National Cancer Institute, National Institutes of Health, National Cancer Institute, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Gianluca Fulgenzi

    Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jodi Becker

    Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Colleen Barrick

    Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Mary Ellen Palko

    Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Skyler Kuhn

    Collaborative Bioinformatics Resource, National Cancer Institute, National Institutes of Health, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Vishal Koparde

    Collaborative Bioinformatics Resource, National Cancer Institute, National Institutes of Health, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Maggie Cam

    Collaborative Bioinformatics Resource, National Cancer Institute, National Institutes of Health, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Sudhirkumar Yanpallewar

    Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Shalini Oberdoerffer

    Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Lino Tessarollo

    Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, United States
    For correspondence
    tessarol@mail.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6420-772X

Funding

National Cancer Center (Intramural Research Program)

  • Maggie Cam

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experimental procedures followed the National Institutes of Health Guidelines for animal care and use, and were approved by the NCI-Frederick Animal Care and Use Committee.

Reviewing Editor

  1. Moses V Chao, New York University Langone Medical Center, United States

Publication history

  1. Received: June 25, 2019
  2. Accepted: July 25, 2019
  3. Accepted Manuscript published: August 20, 2019 (version 1)
  4. Version of Record published: August 29, 2019 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Francesco Tomassoni-Ardori
  2. Gianluca Fulgenzi
  3. Jodi Becker
  4. Colleen Barrick
  5. Mary Ellen Palko
  6. Skyler Kuhn
  7. Vishal Koparde
  8. Maggie Cam
  9. Sudhirkumar Yanpallewar
  10. Shalini Oberdoerffer
  11. Lino Tessarollo
(2019)
RbFox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels
eLife 8:e49673.
https://doi.org/10.7554/eLife.49673

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