Document Type

Article

Publication Date

8-2015

Identifier

DOI: 10.1016/j.bbadis.2015.04.016

Abstract

Alternative splicing (AS) plays an important role in regulating mammalian heart development, but a link between misregulated splicing and congenital heart defects (CHDs) has not been shown. We reported that more than 50% of genes associated with heart development were alternatively spliced in the right ventricle (RV) of infants with tetralogy of Fallot (TOF). Moreover, there was a significant decrease in the level of 12 small cajal body-specific RNAs (scaRNAs) that direct the biochemical modification of specific nucleotides in spliceosomal RNAs. We sought to determine if scaRNA levels influence patterns of AS and heart development. We used primary cells derived from the RV of infants with TOF to show a direct link between scaRNA levels and splice isoforms of several genes that regulate heart development (e.g., GATA4, NOTCH2, DAAM1, DICER1, MBNL1 and MBNL2). In addition, we used antisense morpholinos to knock down the expression of two scaRNAs (scarna1 and snord94) in zebrafish and saw a corresponding disruption of heart development with an accompanying alteration in splice isoforms of cardiac regulatory genes. Based on these combined results, we hypothesize that scaRNA modification of spliceosomal RNAs assists in fine tuning the spliceosome for dynamic selection of mRNA splice isoforms. Our results are consistent with disruption of splicing patterns during early embryonic development leading to insufficient communication between the first and second heart fields, resulting in conotruncal misalignment and TOF. Our findings represent a new paradigm for determining the mechanisms underlying congenital cardiac malformations.

Journal Title

Biochimica et biophysica acta

Volume

1852

Issue

8

First Page

1619

Last Page

1629

MeSH Keywords

Alternative Splicing; Animals; Animals, Genetically Modified; Cells, Cultured; Coiled Bodies; Embryo, Nonmammalian; Gene Expression Regulation, Developmental; Heart; Heart Defects, Congenital; Humans; Infant; Infant, Newborn; MicroRNAs; Vertebrates; Zebrafish

Keywords

Congenital heart defect; Spliceosome; Splicing; Tetralogy of Fallot; Zebrafish; scaRNA

Comments

This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.

Publisher's Link: https://www.sciencedirect.com/science/article/pii/S0925443915001222?via%3Dihub

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