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RBM4 Modulates Radial Migration via Alternative Splicing of Dab1 during Cortex Development.

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.

SUBMITTER: D D

PROVIDER: S-EPMC5974434 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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RBM4 Modulates Radial Migration via Alternative Splicing of Dab1 during Cortex Development.

D Dhananjaya D Hung Kuan-Yang KY Tarn Woan-Yuh WY

Molecular and cellular biology 20180529 12

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. <i>Rbm4a</i> knockout brain exhibited delayed migration of late-born neurons. Using <i>in utero</i> electroporation, we confi ...[more]

PMID: 29581187

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Project description:Rationale: The adult skeletal muscle can self-repair efficiently following mechanical or pathological damage due to its remarkable regenerative capacity. However, regulatory mechanisms underlying muscle regeneration are complicated and have not been fully elucidated. Alternative splicing (AS) is a major mechanism responsible for post-transcriptional regulation. Many aberrant AS events have been identified in patients with muscular dystrophy which is accompanied by abnormal muscle regeneration. However, little is known about the correlation between AS and muscle regeneration. It has been reported that RNA binding motif protein 24 (Rbm24), a tissue-specific splicing factor, is involved in embryo myogenesis while the role of Rbm24 in adult myogenesis (also called muscle regeneration) is poorly understood. Methods: To investigate the role of Rbm24 in adult skeletal muscle, we generated Rbm24 conditional knockout mice and satellite cell-specific knockout mice. Furthermore, a cardiotoxin (CTX)-induced injury model was utilized to assess the effects of Rbm24 on skeletal muscle regeneration. Genome-wide RNA-Seq was performed to identify the changes in AS following loss of Rbm24. Results: Rbm24 knockout mice displayed abnormal regeneration 4 months after tamoxifen treatment. Using RNA-Seq, we found that Rbm24 regulated a complex network of AS events involved in multiple biological processes, including myogenesis, muscle regeneration and muscle hypertrophy. Moreover, using a CTX-induced injury model, we showed that loss of Rbm24 in skeletal muscle resulted in myogenic fusion and differentiation defects and significantly delayed muscle regeneration. Furthermore, satellite cell-specific Rbm24 knockout mice recapitulated the defects in regeneration seen in the global Rbm24 knockout mice. Importantly, we demonstrated that Rbm24 regulated AS of Mef2d, Naca, Rock2 and Lrrfip1 which are essential for myogenic differentiation and muscle regeneration. Conclusions: The present study demonstrated that Rbm24 regulates dynamic changes in AS and is essential for adult skeletal muscle regeneration.

Dataset Information

RBM4 Modulates Radial Migration via Alternative Splicing of Dab1 during Cortex Development.

Publications

RBM4 Modulates Radial Migration via Alternative Splicing of Dab1 during Cortex Development.

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