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Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency
A molecular and functional link between neurotrophin signaling and cerebellar foliation is lacking. Here we show that constitutive knockout of two homologous genes encoding the RNA binding protein RBM4 results in foliation defects at cerebellar lobules VI–VII and delayed motor learning in mice. More...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10480162/ https://www.ncbi.nlm.nih.gov/pubmed/37670183 http://dx.doi.org/10.1038/s42003-023-05294-z |
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author | Tsai, Yu-Young Shen, Chiu-Lun D, Dhananjaya Tsai, Ching-Yen Tarn, Woan-Yuh |
author_facet | Tsai, Yu-Young Shen, Chiu-Lun D, Dhananjaya Tsai, Ching-Yen Tarn, Woan-Yuh |
author_sort | Tsai, Yu-Young |
collection | PubMed |
description | A molecular and functional link between neurotrophin signaling and cerebellar foliation is lacking. Here we show that constitutive knockout of two homologous genes encoding the RNA binding protein RBM4 results in foliation defects at cerebellar lobules VI–VII and delayed motor learning in mice. Moreover, the features of Rbm4 double knockout (dKO), including impaired differentiation of cerebellar granule cells and dendritic arborization of Purkinje cells, are reminiscent of neurotrophin deficiency. Loss of RBM4 indeed reduced brain-derived neurotrophic factor (BDNF). RBM4 promoted the expression of BDNF and full-length TrkB, implicating RBM4 in efficient BDNF-TrkB signaling. Finally, prenatal supplementation with 7,8-dihydroxyflavone, a TrkB agonist, restored granule cell differentiation, Purkinje cell dendritic complexity and foliation—the intercrural fissure in particular—in the neonatal cerebellum of Rbm4dKO mice, which also showed improved motor learning in adulthood. This study provides evidence that prenatal activation of TrkB signaling ameliorates cerebellar malformation caused by BDNF deficiency. |
format | Online Article Text |
id | pubmed-10480162 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-104801622023-09-07 Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency Tsai, Yu-Young Shen, Chiu-Lun D, Dhananjaya Tsai, Ching-Yen Tarn, Woan-Yuh Commun Biol Article A molecular and functional link between neurotrophin signaling and cerebellar foliation is lacking. Here we show that constitutive knockout of two homologous genes encoding the RNA binding protein RBM4 results in foliation defects at cerebellar lobules VI–VII and delayed motor learning in mice. Moreover, the features of Rbm4 double knockout (dKO), including impaired differentiation of cerebellar granule cells and dendritic arborization of Purkinje cells, are reminiscent of neurotrophin deficiency. Loss of RBM4 indeed reduced brain-derived neurotrophic factor (BDNF). RBM4 promoted the expression of BDNF and full-length TrkB, implicating RBM4 in efficient BDNF-TrkB signaling. Finally, prenatal supplementation with 7,8-dihydroxyflavone, a TrkB agonist, restored granule cell differentiation, Purkinje cell dendritic complexity and foliation—the intercrural fissure in particular—in the neonatal cerebellum of Rbm4dKO mice, which also showed improved motor learning in adulthood. This study provides evidence that prenatal activation of TrkB signaling ameliorates cerebellar malformation caused by BDNF deficiency. Nature Publishing Group UK 2023-09-05 /pmc/articles/PMC10480162/ /pubmed/37670183 http://dx.doi.org/10.1038/s42003-023-05294-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Tsai, Yu-Young Shen, Chiu-Lun D, Dhananjaya Tsai, Ching-Yen Tarn, Woan-Yuh Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency |
title | Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency |
title_full | Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency |
title_fullStr | Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency |
title_full_unstemmed | Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency |
title_short | Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency |
title_sort | activation of trkb signaling mitigates cerebellar anomalies caused by rbm4-bdnf deficiency |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10480162/ https://www.ncbi.nlm.nih.gov/pubmed/37670183 http://dx.doi.org/10.1038/s42003-023-05294-z |
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