RBM4 promotes neuronal differentiation and neurite outgrowth by modulating Numb isoform expression

Tarn, Woan‐Yuh; Kuo, Hung‐Che; Yu, Hsin-I; Liu, Shin-Wu; Tseng, Ching-Tzu; Dhananjaya, D; Hung, Kuan-Yang; Tu, Chi-Chiang; Chang, Shuo-Hsiu; Huang, Guo-Jen; Chiu, Ing‐Ming

doi:10.1091/mbc.e15-11-0798

Cited by 26 publications

(32 citation statements)

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“…PKM1 is expressed in energy-consuming tissues, including brain and skeletal muscle, whereas PKM2 is expressed more dominantly in embryonic cells (19). We previously observed a change in expression of Pkm isoforms, i.e., from Pkm2 to Pkm1, during neuronal differentiation of mouse embryonal carcinoma P19 cells (1). We thus further explored the significance and mechanism of this isoform switch during development.…”

Section: Resultsmentioning

confidence: 97%

“…Previous studies demonstrated the role of RBM4 in differentiation of muscle and pancreas cells and adipocytes (3)(4)(5). We recently reported that RBM4 is also involved in neuronal differentiation of mouse embryonal carcinoma P19 cells and neural progenitor-derived cells (1). RBM4 promotes the expression of Numb splice isoforms that function during neuronal differentiation as well as neurite outgrowth.…”

mentioning

confidence: 92%

“…T he splicing regulator RBM4 modulates alternative splicing of a number of transcripts involved in cell differentiation and tumorigenesis (1,2). Previous studies demonstrated the role of RBM4 in differentiation of muscle and pancreas cells and adipocytes (3)(4)(5).…”

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confidence: 99%

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RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M

Hung

et al. 2017

Molecular and Cellular Biology

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RBM4 promotes differentiation of neuronal progenitor cells and neurite outgrowth of cultured neurons via its role in splicing regulation. In this study, we further explored the role of RBM4 in neuronal differentiation. During neuronal differentiation, energy production shifts from glycolysis to oxidative phosphorylation. We found that the splice isoform change of the metabolic enzyme pyruvate kinase M (PKM) from PKM2 to PKM1 occurs during brain development and is impaired in RBM4-deficient brains. The PKM isoform change could be recapitulated in human mesenchymal stem cells (MSCs) during neuronal induction. Using a PKM minigene, we demonstrated that RBM4 plays a direct role in regulating alternative splicing of PKM. Moreover, RBM4 antagonized the function of the splicing factor PTB and induced the expression of a PTB isoform with attenuated splicing activity in MSCs. Overexpression of RBM4 or PKM1 induced the expression of neuronal genes, increased the mitochondrial respiration capacity in MSCs, and, accordingly, promoted neuronal differentiation. Finally, we demonstrated that RBM4 is induced and is involved in the PKM splicing switch and neuronal gene expression during hypoxiainduced neuronal differentiation. Hence, RBM4 plays an important role in the PKM isoform switch and the change in mitochondrial energy production during neuronal differentiation.KEYWORDS alternative splicing, hypoxia, mesenchymal stem cells, neuronal differentiation, pyruvate kinase M T he splicing regulator RBM4 modulates alternative splicing of a number of transcripts involved in cell differentiation and tumorigenesis (1, 2). Previous studies demonstrated the role of RBM4 in differentiation of muscle and pancreas cells and adipocytes (3-5). We recently reported that RBM4 is also involved in neuronal differentiation of mouse embryonal carcinoma P19 cells and neural progenitor-derived cells (1). RBM4 promotes the expression of Numb splice isoforms that function during neuronal differentiation as well as neurite outgrowth. Mesenchymal stem cells (MSCs) are adult bone marrow stromal cells that can differentiate into a variety of cell types, including neurons, and have potential in regenerative therapy for neurological diseases (6). In this study, we assessed whether RBM4 can also modulate neuronal differentiation of MSCs and explored the underlying mechanism.Cellular energy metabolism undergoes a dynamic change during development. In principle, anabolic glycolysis dominates in embryonic stem cells and permits rapid cell proliferation similar to that in cancer cells (7,8). Most adult stem cells exhibit low glycolysis activity in a quiescent state and undertake active glycolysis while proliferat-

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Section: Resultsmentioning

confidence: 97%

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confidence: 92%

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RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M

Hung

et al. 2017

Molecular and Cellular Biology

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“…GREs have been associated to the stabilization of mRNAs 61 and also have been reported as targets of RNA-binding proteins (RBPs) such as CELFs 62 . Among the set of 160 genes with differential inclusion of GRE elements in our neural system, tappAS identified splicing regulators such as Rbm4 (Supplementary Figure 1A), involved in neurogenesis of the mouse embryonic brain 63 , and Tcf12 (Supplementary Figure 1B), known to play an important role in the control of proliferating neural stem cells and progenitor cells during neurogenesis 64 .…”

Section: 'Utr and Cds-varyingmentioning

confidence: 99%

tappAS: a comprehensive computational framework for the analysis of the functional impact of differential splicing

Fuente

Arzalluz-Luque

Tardáguila

et al. 2019

Preprint

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Traditionally, the functional analysis of gene expression data has used pathway and network enrichment algorithms. These methods are usually gene rather than transcript centric and hence fall short to unravel functional roles associated to posttranscriptional regulatory mechanisms such as Alternative Splicing (AS) and Alternative PolyAdenylation (APA), jointly referred here as Alternative Transcript Processing (AltTP). Moreover, short-read RNA-seq has serious limitations to resolve full-length transcripts, further complicating the study of isoform expression. Recent advances in long-read sequencing open exciting opportunities for studying isoform biology and function. However, there are no established bioinformatics methods for the functional analysis of isoform-resolved transcriptomics data to fully leverage these technological advances. Here we present a novel framework for Functional Iso-Transcriptomics analysis (FIT). This framework uses a rich isoform-level annotation database of functional domains, motifs and sites -both coding and noncoding-and introduces novel analysis methods to interrogate different aspects of the functional relevance of isoform complexity. The Functional Diversity Analysis (FDA) evaluates the variability at the inclusion/exclusion of functional domains across annotated transcripts of the same gene. Parameters can be set to evaluate if AltTP partially or fully disrupts functional elements. FDA is a measure of the potential of a multiple isoform transcriptome to have a functional impact. By combining these functional labels with expression data, the Differential Analysis Module evaluates the relative contribution of transcriptional (i.e. gene level) and post-transcriptional (i.e. transcript/protein levels) regulation on the biology of the system. Measures of inclusion of NLS, transmembrane domains or DNA binding motifs, for example.Some of these findings were experimentally validated by others and us.In summary, we propose a novel framework for the functional analysis of transcriptomes at isoform resolution. We anticipate the tappAS tool will be an important resource for the adoption of the Functional Iso-Transcriptomics analysis by functional genomics community.

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“…RBM4 level is reduced in patients affected with fetal Down syndrome (14). We previously reported that RBM4 modulates alternative splicing of the Notch signaling inhibitor Numb and that RBM4-induced Numb isoforms potentiate the expression of the proneurogenesis gene Mash1 and hence promotes differentiation of mouse neuronal progenitor cells (15). In addition, RBM4 modulates the splice isoform switch of pyruvate kinase M (PKM) and thereby elevates mitochondrial oxidative phosphorylation and facilitates neuronal differentiation of mesenchymal stem cells (10).…”

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

Dhananjaya

Hung

Tarn

2018

Molecular and Cellular Biology

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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. knockout brain exhibited delayed migration of late-born neurons. Using electroporation, we confirmed that knockdown of RBM4 impaired cortical neuronal migration. RNA immunoprecipitation with high-throughput sequencing identified (), which encodes a critical reelin signaling adaptor, as a potential target of RBM4. knockout embryonic brain showed altered isoform ratios. Overexpression of RBM4 promoted the inclusion of 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.

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RBM4 promotes neuronal differentiation and neurite outgrowth by modulating Numb isoform expression

Cited by 26 publications

References 35 publications

RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M

RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M

tappAS: a comprehensive computational framework for the analysis of the functional impact of differential splicing

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

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