A Role for the RNA-Binding Protein, hermes, in the Regulation of Heart Development

Gerber, Wendy V.; Vokes, Steven A.; Zearfoss, N. Ruth; Krieg, Paul A.

doi:10.1006/dbio.2002.0678

Cited by 48 publications

(55 citation statements)

References 51 publications

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“…Importantly, we could rescue these defects by injecting normal versions of the transcripts, at least partially. Previously, we and others have implicated splicing proteins in developmental regulatory events in Xenopus, but it has been difficult to identify the primary targets (Gerber et al 2002;Liu and Harland 2005). Here we used the phenotypes of the affected embryos to identify some misregulated components and extended this using RNA-seq to show that we can analyze missplicing in an unbiased manner.…”

Section: Discussionmentioning

confidence: 99%

fus/TLS orchestrates splicing of developmental regulators during gastrulation

Dichmann

Harland²

2012

Genes Dev.

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Here we investigated the function of the atypical RNA-binding protein fus/TLS (fused in sarcoma/translocated in sarcoma) during early frog development. We found that fus is necessary for proper mRNA splicing of a set of developmental regulatory genes during early frog development and gastrulation. Upon fus knockdown, embryos fail to gastrulate and show mesodermal differentiation defects that we connect to intron retention in fgf8 (fibroblast growth factor 8) and fgfr2 (fgf receptor 2) transcripts. During gastrulation, the animal and marginal regions dissociate, and we show that this is caused, at least in part, by intron retention in cdh1 transcripts. We confirm the specificity of splicing defects at a genomic level using analysis of RNA sequencing (RNA-seq) and show that 3%-5% of all transcripts display intron retention throughout the pre-mRNA. By analyzing gene ontology slim annotations, we show that the affected genes are enriched for developmental regulators and therefore represent a biologically coherent set of targets for fus regulation in embryogenesis. This shows that fus is central to embryogenesis and may provide information on its function in neurodegenerative disease.[Keywords: Xenopus; fus; splicing; signaling; embryo development; RNA-seq] Supplemental material is available for this article. Pre-mRNA splicing, alternative and constitutive, is catalyzed by the spliceosome that contains five small nuclear ribonucleoproteins (snRNPs): U1, U2, U4, U5, and U6. Splicing occurs in a stepwise fashion, and a series of distinct complexes form in the process at the 59 and 39 splice sites and branch point site (Wahl et al. 2009). However, these sequences are short and poorly conserved. During splicing, the spliceosome must therefore succeed in recognizing and joining splice sites that are surrounded by numerous similar sequences and often separated by considerable distances. Further complicating the task, the interactions between the snRNPs and the pre-mRNA are generally weak and rely for specificity on numerous auxiliary proteins that interact with the core snRNPs. This general principle of multiple interactions is important not only for precisely finding correct splice pairs, but also for the flexibility necessary for alternative splice site selection.Comprehensive analysis of purified early spliceosomal complexes shows that they consist of at least 85 and perhaps as many as 150-300 different proteins with a combined mass of 2.7 MDa. Many of these function in the enzymatic and conformational changes that occur during splicing, while others are involved in exon and intron definition by binding to splicing enhancers or silencers present in the pre-mRNA. For example, members of the serine-arginine-rich splice factors (SR proteins) frequently bind sequences in exons and stimulate exon inclusion by stabilizing U1 and U2 binding to the 59 splice site and branch point site, respectively. Other well-known splicing regulators are the heterologous nuclear RNPs (hnRNPs) that generally repress exon inclusion and hence co...

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Section: Discussionmentioning

confidence: 99%

fus/TLS orchestrates splicing of developmental regulators during gastrulation

Dichmann

Harland²

2012

Genes Dev.

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“…RBPMS expression in embryos and adult tissues has been studied by various methodologies in several vertebrate species supporting expression in heart and retinal ganglion cells (Shimamoto et al 1996;Gerber et al 2002;Su et al 2004;Wang et al 2008;Kwong et al 2010;Derrien et al 2012). A survey of a limited set of adult human tissues by poly(A) RNAseq indicated that RBPMS was the most highly expressed in the prostate, followed by colon, adipose tissue, and heart, with RBPMS being higher expressed than RBPMS2 in most tissues (Derrien et al 2012;Supplemental Fig.…”

Section: Rbpms Family Member Expression Patternsmentioning

confidence: 99%

“…Dysregulation of RBPMS family proteins has been reported in cancer (Skawran et al 2008;Miller and Stamatoyannopoulos 2010;Drozdov et al 2012;Hapkova et al 2013; http://www.cbioportal.org/public-portal/) and chronic intestinal pseudo-obstruction (Notarnicola et al 2012). Manipulation of RBPMS levels during embryogenesis suggested functions in X. laevis oocyte maturation (Zearfoss et al 2003), heart and kidney development (Gerber et al 2002), and retinal ganglion cell development (Hornberg et al 2013). In X. laevis RBPMS regulated cleavage of vegetal blastomeres in early embryogenesis (Zearfoss et al 2004) and was suggested to control mRNA processing (Gerber et al 2002;Song et al 2007) and transport of mRNAs along the axon to the axon terminal of retinal ganglion cells (Hornberg et al 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Manipulation of RBPMS levels during embryogenesis suggested functions in X. laevis oocyte maturation (Zearfoss et al 2003), heart and kidney development (Gerber et al 2002), and retinal ganglion cell development (Hornberg et al 2013). In X. laevis RBPMS regulated cleavage of vegetal blastomeres in early embryogenesis (Zearfoss et al 2004) and was suggested to control mRNA processing (Gerber et al 2002;Song et al 2007) and transport of mRNAs along the axon to the axon terminal of retinal ganglion cells (Hornberg et al 2013).…”

Section: Introductionmentioning

confidence: 99%

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Identification of the RNA recognition element of the RBPMS family of RNA-binding proteins and their transcriptome-wide mRNA targets

Farazi

Leonhardt

Mukherjee

et al. 2014

RNA

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Recent studies implicated the RNA-binding protein with multiple splicing (RBPMS) family of proteins in oocyte, retinal ganglion cell, heart, and gastrointestinal smooth muscle development. These RNA-binding proteins contain a single RNA recognition motif (RRM), and their targets and molecular function have not yet been identified. We defined transcriptome-wide RNA targets using photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) in HEK293 cells, revealing exonic mature and intronic pre-mRNA binding sites, in agreement with the nuclear and cytoplasmic localization of the proteins. Computational and biochemical approaches defined the RNA recognition element (RRE) as a tandem CAC trinucleotide motif separated by a variable spacer region. Similar to other mRNA-binding proteins, RBPMS family of proteins relocalized to cytoplasmic stress granules under oxidative stress conditions suggestive of a support function for mRNA localization in large and/or multinucleated cells where it is preferentially expressed.

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“…Moreover, Nkx2.5 expression is regulated by both XHMGA2 and Smads (Monzen et al, 2008). The RNA-binding protein hermes also regulates Nkx2.5 expression (Gerber et al, 2002). Tbx5, Tbx20, myocardin, and islet1 are transcription factors that interact with Nkx2.5 and GATAs and regulate gene expression in the precardiac region (Stennard et al, 2003, Small et al, 2005, Brade et al, 2007.…”

Section: In Vitro Differentiation Of Pronephros and Molecular Analysimentioning

confidence: 99%

In vitro organogenesis from undifferentiated cells in Xenopus

Asashima

Ito

Chan

et al. 2009

Developmental Dynamics

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Amphibians have been used for over a century as experimental animals. In the field of developmental biology in particular, much knowledge has been accumulated from studies on amphibians, mainly because they are easy to observe and handle. Xenopus laevis is one of the most intensely investigated amphibians in developmental biology at the molecular level. Thus, Xenopus is highly suitable for studies on the mechanisms of organ differentiation from not only a single fertilized egg, as in normal development, but also from undifferentiated cells, as in the case of in vitro organogenesis. Based on the established in vitro organogenesis methods, we have identified many genes that are indispensable for normal development in various organs. These experimental systems are useful for investigations of embryonic development and for advancing regenerative medicine. Developmental Dynamics 238:1309 -1320, 2009.

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A Role for the RNA-Binding Protein, hermes, in the Regulation of Heart Development

Cited by 48 publications

References 51 publications

fus/TLS orchestrates splicing of developmental regulators during gastrulation

fus/TLS orchestrates splicing of developmental regulators during gastrulation

Identification of the RNA recognition element of the RBPMS family of RNA-binding proteins and their transcriptome-wide mRNA targets

In vitro organogenesis from undifferentiated cells in Xenopus

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