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Review
. 2013 Nov;45(11):2467-78.
doi: 10.1016/j.biocel.2013.08.008. Epub 2013 Aug 20.

RNA binding proteins in the regulation of heart development

Yotam Blech-Hermoni  1 , Andrea N Ladd
Affiliations
Review

RNA binding proteins in the regulation of heart development

Yotam Blech-Hermoni et al. Int J Biochem Cell Biol. 2013 Nov.

Erratum in

  • Int J Biochem Cell Biol. 2014 Oct;55:348

Abstract

In vivo, RNA molecules are constantly accompanied by RNA binding proteins (RBPs), which are intimately involved in every step of RNA biology, including transcription, editing, splicing, transport and localization, stability, and translation. RBPs therefore have opportunities to shape gene expression at multiple levels. This capacity is particularly important during development, when dynamic chemical and physical changes give rise to complex organs and tissues. This review discusses RBPs in the context of heart development. Since the targets and functions of most RBPs--in the heart and at large--are not fully understood, this review focuses on the expression and roles of RBPs that have been implicated in specific stages of heart development or developmental pathology. RBPs are involved in nearly every stage of cardiogenesis, including the formation, morphogenesis, and maturation of the heart. A fuller understanding of the roles and substrates of these proteins could ultimately provide attractive targets for the design of therapies for congenital heart defects, cardiovascular disease, or cardiac tissue repair.

Keywords: 3′ UTR; 3′ untranslated region; AVC; CELF; CHAMP; CUG-BP, Elav-like family; Csm; DGCR8; DGS; DM; Development; DiGeorge Syndrome; DiGeorge Syndrome critical region gene 8; EMT; ESRP; FXR1; HERMES; Heart; KH domain; MBNL; MET; Morphogenesis; OFT; PTB; RBFOX; RBM; RBP; RISC; RNA binding Fox-1 homolog; RNA binding motif; RNA binding protein; RNA processing; RNA recognition motif; RNA-induced silencing complex; RRM; RS domain; Regulation; SRSF; STAR; arginine/serine-rich domain; atrioventricular canal; cardiac helicase activated by MEF2 protein; cardiac-specific isoform of Mov10l1; dystrophia myotonica (myotonic dystrophy); epithelial splicing regulatory protein; epithelial-to-mesenchymal transition; fragile X mental retardation autosomal homolog 1; heart and RRM expressed sequence; held out wings; heterogeneous nuclear ribonucleoprotein; hnRNP; hnRNP K homology domain; how; mesenchymal-to-epithelial transition; miRNA; microRNA; muscleblind-like; outflow tract; polypyrimidine tract binding protein; serine/arginine-rich splicing factor; signal transduction and activation of RNA.

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Figures

Figure 1
Figure 1. Mechanisms of RBP-mediated post-transcriptional regulation
Schematic representations of mechanisms by which a number of proteins described in this review have been shown to regulate gene expression. Note that these are provided as examples; an exhaustive survey of RBP-mediated regulatory mechanisms is beyond the scope of this review. (1) RBFOX proteins regulate a variety of alternative splicing events by binding within introns flanking alternative exons. Binding upstream of an exon leads to skipping of that exon, while binding downstream of an exon leads to its inclusion (De Craene and Berx, 2013). (2) CELF2 directs the editing of a cytidine in the Apob transcript by binding to an AU-rich sequence element upstream of the editing site and recruiting ACF, a component of the editing machinery (Anant et al., 2001). (3) MBNL2 regulates the transport and localization of the Itga2 transcript to the plasma membrane by binding to a zipcode sequence in the 3′ UTR of the transcript (Adereth et al., 2005). (4) Multiple mechanisms have been proposed for how AUF1 regulates the stability of target transcripts, including the recruitment of the PARN deadenylase, leading to loss of the poly-A tail and rapid degradation of the RNA (White et al., 2013). (5) CELF1 enhances translation of the p21 transcript by antagonizing a regulatory protein, CRT, which normally blocks ribosome loading (Iakova et al., 2004).
Figure 2
Figure 2. RNA binding proteins have been implicated in the formation, morphogenesis, and maturation of the heart
The primitive heart tube forms from precardiac mesoderm within the cardiac crescent. The heart tube undergoes extensive morphogenesis, including cardiac looping, endocardial cushion formation and remodeling, and myocardial trabeculation and compaction. Although the architecture of the heart is established during embryogenesis, maturation of the heart continues through postnatal life. RNA binding proteins that have been implicated in specific steps of heart development are indicated in blue. Abbreviations: OFT, outflow tract; RV, right ventricle; LV, left ventricle; SA, sinoatrial segment; atr, common atrium; AVC, atrioventricular canal; LA, left atrium; RA, right atrium; vc, vena cava; ao, aorta; pa, pulmonary artery.
Figure 3
Figure 3. Domain structure of RNA binding proteins implicated in regulation of heart development
Schematic representations of the type and position of important domains within the RNA binding proteins described in this review are shown. RNA binding domains and other domains characteristic of these RNA binding protein families are shown in color; other conserved domains are shown in black and white. Proteins and domains are not drawn to scale. Molecular functions of these RNA binding proteins within the heart are indicated, if known; additional functions of these proteins that have been demonstrated in other tissue types are not shown. The domain structures of these proteins are highly conserved across vertebrate species, and the depicted structures represent all homologs described in the text. Note that the structure of QK/How is conserved from human to fly, whereas to date CHAMP/Csm has only been described in mammals.
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