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Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels.
Elife 2019; 8E

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.

Authors+Show Affiliations

Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, United States.Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, United States.Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, United States.Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, United States.Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, United States.CCR Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, United States. Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, United States.CCR Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, United States. Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, United States.CCR Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, United States. Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, United States.Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, United States.Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, United States.Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31429825

Citation

Tomassoni-Ardori, Francesco, et al. "Rbfox1 Up-regulation Impairs BDNF-dependent Hippocampal LTP By Dysregulating TrkB Isoform Expression Levels." ELife, vol. 8, 2019.
Tomassoni-Ardori F, Fulgenzi G, Becker J, et al. Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels. Elife. 2019;8.
Tomassoni-Ardori, F., Fulgenzi, G., Becker, J., Barrick, C., Palko, M. E., Kuhn, S., ... Tessarollo, L. (2019). Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels. ELife, 8, doi:10.7554/eLife.49673.
Tomassoni-Ardori F, et al. Rbfox1 Up-regulation Impairs BDNF-dependent Hippocampal LTP By Dysregulating TrkB Isoform Expression Levels. Elife. 2019 Aug 20;8 PubMed PMID: 31429825.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels. AU - Tomassoni-Ardori,Francesco, AU - Fulgenzi,Gianluca, AU - Becker,Jodi, AU - Barrick,Colleen, AU - Palko,Mary Ellen, AU - Kuhn,Skyler, AU - Koparde,Vishal, AU - Cam,Maggie, AU - Yanpallewar,Sudhirkumar, AU - Oberdoerffer,Shalini, AU - Tessarollo,Lino, Y1 - 2019/08/20/ PY - 2019/06/25/received PY - 2019/07/25/accepted PY - 2019/8/21/pubmed PY - 2019/8/21/medline PY - 2019/8/21/entrez KW - RNA regulation KW - RbFox KW - TrkB KW - mouse KW - neuroscience KW - neurotrophins JF - eLife JO - Elife VL - 8 N2 - 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. SN - 2050-084X UR - https://www.unboundmedicine.com/medline/citation/31429825/RbFox1_up-regulation_impairs_BDNF-dependent_hippocampal_LTP_by_dysregulating_TrkB_isoform_expression_levels L2 - https://doi.org/10.7554/eLife.49673 DB - PRIME DP - Unbound Medicine ER -