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Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels

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 disorder...

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Autores principales: Tomassoni-Ardori, Francesco, Fulgenzi, Gianluca, Becker, Jodi, Barrick, Colleen, Palko, Mary Ellen, Kuhn, Skyler, Koparde, Vishal, Cam, Maggie, Yanpallewar, Sudhirkumar, Oberdoerffer, Shalini, Tessarollo, Lino
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715404/
https://www.ncbi.nlm.nih.gov/pubmed/31429825
http://dx.doi.org/10.7554/eLife.49673
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author Tomassoni-Ardori, Francesco
Fulgenzi, Gianluca
Becker, Jodi
Barrick, Colleen
Palko, Mary Ellen
Kuhn, Skyler
Koparde, Vishal
Cam, Maggie
Yanpallewar, Sudhirkumar
Oberdoerffer, Shalini
Tessarollo, Lino
author_facet Tomassoni-Ardori, Francesco
Fulgenzi, Gianluca
Becker, Jodi
Barrick, Colleen
Palko, Mary Ellen
Kuhn, Skyler
Koparde, Vishal
Cam, Maggie
Yanpallewar, Sudhirkumar
Oberdoerffer, Shalini
Tessarollo, Lino
author_sort Tomassoni-Ardori, Francesco
collection PubMed
description 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.
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spelling pubmed-67154042019-09-03 Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels Tomassoni-Ardori, Francesco Fulgenzi, Gianluca Becker, Jodi Barrick, Colleen Palko, Mary Ellen Kuhn, Skyler Koparde, Vishal Cam, Maggie Yanpallewar, Sudhirkumar Oberdoerffer, Shalini Tessarollo, Lino eLife Neuroscience 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. eLife Sciences Publications, Ltd 2019-08-20 /pmc/articles/PMC6715404/ /pubmed/31429825 http://dx.doi.org/10.7554/eLife.49673 Text en http://creativecommons.org/publicdomain/zero/1.0/ http://creativecommons.org/publicdomain/zero/1.0/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 (http://creativecommons.org/publicdomain/zero/1.0/) .
spellingShingle Neuroscience
Tomassoni-Ardori, Francesco
Fulgenzi, Gianluca
Becker, Jodi
Barrick, Colleen
Palko, Mary Ellen
Kuhn, Skyler
Koparde, Vishal
Cam, Maggie
Yanpallewar, Sudhirkumar
Oberdoerffer, Shalini
Tessarollo, Lino
Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels
title Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels
title_full Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels
title_fullStr Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels
title_full_unstemmed Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels
title_short Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels
title_sort rbfox1 up-regulation impairs bdnf-dependent hippocampal ltp by dysregulating trkb isoform expression levels
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715404/
https://www.ncbi.nlm.nih.gov/pubmed/31429825
http://dx.doi.org/10.7554/eLife.49673
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