Affiliation:
1. Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan
2. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
Abstract
ABSTRACT
The RNA-binding motif 4 (RBM4) protein participates in cell differentiation via its role in regulating the expression of 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 with high-throughput 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 polypyrimidine tract-binding protein 1 (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 RBM4-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.
Funder
Ministry of Science and Technology, Taiwan
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
20 articles.
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