Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency
Abstract 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 m...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05294-z |
| _version_ | 1797557126578569216 |
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| author | Yu-Young Tsai Chiu-Lun Shen Dhananjaya D Ching-Yen Tsai Woan-Yuh Tarn |
| author_facet | Yu-Young Tsai Chiu-Lun Shen Dhananjaya D Ching-Yen Tsai Woan-Yuh Tarn |
| author_sort | Yu-Young Tsai |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-10T17:12:54Z |
| format | Article |
| id | doaj.art-1c217a2f02ac4fb4867bf3163e0182ea |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-10T17:12:54Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-1c217a2f02ac4fb4867bf3163e0182ea2023-11-20T10:35:10ZengNature PortfolioCommunications Biology2399-36422023-09-016111410.1038/s42003-023-05294-zActivation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiencyYu-Young Tsai0Chiu-Lun Shen1Dhananjaya D2Ching-Yen Tsai3Woan-Yuh Tarn4Institute of Biomedical Sciences, Academia SinicaInstitute of Biomedical Sciences, Academia SinicaInstitute of Biomedical Sciences, Academia SinicaInstitute of Molecular Biology, Academia SinicaInstitute of Biomedical Sciences, Academia SinicaAbstract 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.https://doi.org/10.1038/s42003-023-05294-z |
| spellingShingle | Yu-Young Tsai Chiu-Lun Shen Dhananjaya D Ching-Yen Tsai Woan-Yuh Tarn Activation of TrkB signaling mitigates cerebellar anomalies caused by Rbm4-Bdnf deficiency Communications Biology |
| 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 |
| url | https://doi.org/10.1038/s42003-023-05294-z |
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