RBM4 is involved in brain development via regulating alternative splicing
| Autor: | Dhananjaya D, 何安亞 |
|---|---|
| Rok vydání: | 2018 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 106 The RNA-binding motif 4 (RBM4) protein participates in cell differentiation via its role in regulating the expression of or tissue-specific or developmentally regulated mRNA splice isoforms. RBM4 is expressed in embryonic brain during development; it is initially enriched in the ventricular zone/subventricular zone and subsequently distributed throughout the cerebral cortex. Rbm4a knockout brain exhibited delayed migration of late-born neurons. Using in utero electroporation, we confirmed that knockdown of RBM4 impaired cortical neuronal migration. RNA immunoprecipitation-sequencing identified Disabled-1 (Dab1), which encodes a critical Reelin signaling adaptor, as a potential target of RBM4. Rbm4a knockout embryonic brain showed altered Dab1 isoform ratios. Overexpression of RBM4 promoted the inclusion of Dab1 exons 7 and 8 (7/8), whereas its antagonist PTBP1 acted in an opposite manner. RBM4 directly counteracted the effect of PTBP1 on exon 7/8 selection. Finally, we showed that the full-length Dab1, but not exon 7/8-truncated Dab1, rescued neuronal migration defects in RBM4a-depleted neurons, indicating that RBM4 plays a role in neuronal migration via modulating the expression of Dab1 splice isoforms. Our findings imply that RBM4 is necessary during brain development and that its deficiency may lead to developmental brain abnormality. To understand more about the role of RBM4 in brain development, we generated conventional Rbm4a/b knockout mouse model. Adult Rbm4a/b knockout mice showed reduced body size and displayed multiple phenotypic abnormalities. The Rbm4a/b null cerebellum at postnatal day 10 particularly lost the posterior lobe (VI-VII), and had thicker external granule layer and stunted Purkinje cell dendrites. Investigation into how Rbm4 deletion causes developmental defects of cerebellum is underway. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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