RbFox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels
- National Cancer Institute, United States
- 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.
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Co-regulation of splicing by Rbfox1 and hnRNP MNCBI Gene Expression Omnibus, GSE71468.
Article and author information
Author details
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
- Moses V Chao, New York University Langone Medical Center, United States
Publication history
- Received: June 25, 2019
- Accepted: July 25, 2019
- Accepted Manuscript published: August 20, 2019 (version 1)
- 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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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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