scaRNAs regulate splicing and vertebrate heart development

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1852

Article

Patil, Prakash¹  Kibiryeva, Nataliya²  Uechi, Tamayo¹  Marshall, Jennifer²  O'Brien, James E., Jr.²  Artman, Michael³  Kenmochi, Naoya¹  Bittel, Douglas C.² 

[1] Miyazaki Univ, Frontier Sci Res Ctr, Miyazaki, Japan

[2] Univ Missouri, Sch Med, Childrens Mercy Hosp, Ward Family Heart Ctr, Kansas City, MO 64108 USA

[3] Univ Missouri, Sch Med, Childrens Mercy Hosp, Dept Pediat, Kansas City, MO 64108 USA

关键词: Congenital heart defect;    Tetralogy of Fallot;    Splicing;    Spliceosome;    scaRNA;    Zebrafish;   

DOI  :  10.1016/j.bbadis.2015.04.016

来源: Elsevier

【 摘 要 】

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. (C) 2015 The Authors. Published by Elsevier B.V.

【 授权许可】

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