Abstract 431: ScaRNAs Regulate Cardiac Differentiation and Development by Fine Tuning the Spliceosome

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Douglas C Bittel ◽  
Brenda Rongish ◽  
Nataliya Kibiryeva ◽  
Michael Filla ◽  
Jennifer Marshall ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Right Ventricle ◽  
Heart Development ◽  
Cardiac Development ◽  
Developmental Regulation ◽  
Cardiac Differentiation ◽  
Fine Tuning ◽  
Cajal Body ◽  
Direct Role ◽  
The Right

Alternative splicing (AS) of mRNA adds diversity to the proteome and precise regulation of AS is essential for proper development. We recently showed that multiple genes critical for heart development are irregularly spliced in the right ventricle of babies with tetralogy of Fallot (TOF). We also observed reduced expression of several noncoding small cajal body associated RNAs (scaRNAs). scaRNAs direct the biochemical modification of spliceosomal RNAs and are essential for the stability and function of the spliceosome. Our results provide compelling evidence for a direct role of scaRNAs in regulating splicing of genes that are critical for heart development. To further explore this novel paradigm of developmental regulation, we analyzed the transcriptome of stem cells as they differentiated to beating cardiomyocytes. We observed significant alternative splicing with respect to timepoint (with Bonferroni correction and fdr of 5%) in 3,165 of 20,301 (15.6%) total genes. Importantly, there were 79 alternatively spliced genes among 213 genes (37.1%) known to be critical for heart development. This is a significant enrichment in the cardiac network genes (p<0.001). Most of the alternative isoforms are known protein coding variants. In addition, we saw changes in expression of several scaRNAs. scaRNA1 is reduced in the right ventricle of children with TOF and we targeted it for knockdown in the quail embryo model system. Preliminary results revealed dramatic alterations in cardiac morphogenesis and embryonic lethality. At higher levels of the antisense oligo, cells appeared to undergo apoptosis, aggregated inappropriately and failed to gastrulate. Lower concentrations resulted in initiation of gastrulation with some cells from the cardiac lineage traversing the embryonic milieu to contribute to the heart and other organs. Interestingly, these cells appeared to lack protrusive phenotypes, and may be passively moved by neighboring groups of non-electroporated motile cells. Taken together, our results suggest scaRNAs are necessary to maintain the fidelity of the spliceosome and thus play an important role in vertebrate heart development. These observations provide additional new insights into regulatory mechanisms underlying cardiac development.

Cleft mitral valve in transposition with intact ventricular septum

2004 ◽  
Vol 14 (5) ◽  
pp. 550-552 ◽  
Author(s):  
Samuel Menahem ◽  
Robert H. Anderson
Keyword(s):  
Mitral Valve ◽  
Right Ventricle ◽  
Cardiac Development ◽  
Current Knowledge ◽  
Ventricular Septum ◽  
Short Axis ◽  
Intact Ventricular Septum ◽  
Left Hand ◽  
End Point ◽  
The Right

We describe two cases of an isolated cleft of the mitral valve in transposition with intact ventricular septum. The cleft is positioned leftward in the pulmonary leaflet, at about 2 o’clock, when viewed from below looking at the cardiac short axis with the right ventricle to one’s left hand. Such clefts, when seen in the Taussig-Bing malformation are also positioned leftward.In keeping with our current knowledge of cardiac development, our cases provide further evidence that transposition with an intact ventricular septum is the end-point of the Taussig-Bing spectrum.

scholarly journals An alternatively spliced zebrafish jnk1a transcript has an essential and non-redundant role in development of the first heart field derived proximal ventricular chamber

2019 ◽  
Author(s):  
A Santos-Ledo ◽  
S Washer ◽  
T Dhanaseelan ◽  
P Chrystal ◽  
T Papoutsi ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Heart Development ◽  
Planar Cell Polarity ◽  
Cardiac Development ◽  
Single Gene ◽  
Jun Kinase ◽  
Downstream Effectors ◽  
Heart Malformation ◽  
Alternatively Spliced ◽  
First Heart Field

AbstractAlternative splicing is a ubiquitous mechanism for producing different mRNA species from a single gene, resulting in proteomic diversity. Despite potential for regulating embryogenesis, its developmental role remains under-investigated. The Jun kinase (Jnk) genes, considered downstream effectors of the non-canonical Wnt planar cell polarity pathway, utilise extensive and evolutionarily-conserved alternative splicing. Although many PCP members are associated with heart malformation, the role of Jnk genes in cardiac development, and specifically which alternatively spliced transcripts orchestrate these processes, remain unknown. In this study we exploit the jnk1 duplication and subspecialisation found in zebrafish to reveal an essential and non-redundant requirement for jnk1a in cardiac development. We characterise alternatively spliced jnk1a/jnk1b transcripts and demonstrate that hypoplasia of the proximal ventricular component, which corresponds to human hypoplastic left ventricle, can only be rescued by the jnk1a Ex7 Lg transcript. These studies highlight the importance of Jnk signalling and alternative splicing in heart development

microRNAs in cardiac development and regeneration

2013 ◽  
Vol 125 (4) ◽  
pp. 151-166 ◽  
Author(s):  
Enzo R. Porrello
Keyword(s):  
Gene Expression ◽  
Heart Development ◽  
Regulatory Networks ◽  
Cardiac Development ◽  
Regulation Of Gene Expression ◽  
Cardiac Regeneration ◽  
Cardiac Differentiation ◽  
Evolutionarily Conserved ◽  
Post Transcriptional Regulation ◽  
Therapeutic Possibilities

Heart development involves the precise orchestration of gene expression during cardiac differentiation and morphogenesis by evolutionarily conserved regulatory networks. miRNAs (microRNAs) play important roles in the post-transcriptional regulation of gene expression, and recent studies have established critical functions for these tiny RNAs in almost every facet of cardiac development and disease. The realization that miRNAs are amenable to therapeutic manipulation has also generated considerable interest in the potential of miRNA-based drugs for the treatment of a number of human diseases, including cardiovascular disease. In the present review, I discuss well-established and emerging roles of miRNAs in cardiac development, their relevance to congenital heart disease and unresolved questions in the field for future investigation, as well as emerging therapeutic possibilities for cardiac regeneration.

scholarly journals Bmp Signaling Regulates Hand1 in a Dose-Dependent Manner during Heart Development

2021 ◽  
Vol 22 (18) ◽  
pp. 9835
Author(s):  
Mingjie Zheng ◽  
Shannon Erhardt ◽  
Di Ai ◽  
Jun Wang
Keyword(s):  
Signaling Pathway ◽  
Heart Development ◽  
Cardiac Development ◽  
Regulatory Elements ◽  
Bmp Signaling ◽  
Cardiac Differentiation ◽  
Bhlh Transcription Factor ◽  
Dependent Manner ◽  
Helix Loop Helix ◽  
Dose Dependent

The bone morphogenetic protein (Bmp) signaling pathway and the basic helix–loop–helix (bHLH) transcription factor Hand1 are known key regulators of cardiac development. In this study, we investigated the Bmp signaling regulation of Hand1 during cardiac outflow tract (OFT) development. In Bmp2 and Bmp4loss-of-function embryos with varying levels of Bmp in the heart, Hand1 is sensitively decreased in response to the dose of Bmp expression. In contrast, Hand1 in the heart is dramatically increased in Bmp4 gain-of-function embryos. We further identified and characterized the Bmp/Smad regulatory elements in Hand1. Combined transfection assays and chromatin immunoprecipitation (ChIP) experiments indicated that Hand1 is directly activated and bound by Smads. In addition, we found that upon the treatment of Bmp2 and Bmp4, P19 cells induced Hand1 expression and favored cardiac differentiation. Together, our data indicated that the Bmp signaling pathway directly regulates Hand1 expression in a dose-dependent manner during heart development.

scholarly journals The Apelin receptor enhances Nodal/TGFβ signaling to ensure proper cardiac development

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Ashish R Deshwar ◽  
Serene C Chng ◽  
Lena Ho ◽  
Bruno Reversade ◽  
Ian C Scott
Keyword(s):  
Heart Development ◽  
Cardiac Development ◽  
Cardiac Differentiation ◽  
Tgfβ Signaling ◽  
Cardiac Progenitors ◽  
Early Migration ◽  
Apelin Receptor ◽  
And Migration ◽  
Peptide Agonist ◽  
Fine Tune

The Apelin receptor (Aplnr) is essential for heart development, controlling the early migration of cardiac progenitors. Here we demonstrate that in zebrafish Aplnr modulates Nodal/TGFβ signaling, a key pathway essential for mesendoderm induction and migration. Loss of Aplnr function leads to a reduction in Nodal target gene expression whereas activation of Aplnr by a non-peptide agonist increases the expression of these same targets. Furthermore, loss of Aplnr results in a delay in the expression of the cardiogenic transcription factors mespaa/ab. Elevating Nodal levels in aplnra/b morphant and double mutant embryos is sufficient to rescue cardiac differentiation defects. We demonstrate that loss of Aplnr attenuates the activity of a point source of Nodal ligands Squint and Cyclops in a non-cell autonomous manner. Our results favour a model in which Aplnr is required to fine-tune Nodal output, acting as a specific rheostat for the Nodal/TGFβ pathway during the earliest stages of cardiogenesis.

Comprehensive Quantification of the Right Ventricle: Pediatric Reference Values from 0 to 18 Years

2016 ◽  
Vol 64 (S 02) ◽  
Author(s):  
J. Horst ◽  
A. Karabiyik ◽  
H. Körperich ◽  
M. Fischer ◽  
E. Klusmeier ◽  
...  
Keyword(s):  
Right Ventricle ◽  
Reference Values ◽  
The Right

Right Ventricle Mass Removal from Tricuspid Valve Apparatus: An Unusual Thromboembolic Complication of Severe Ketoacidosis

2016 ◽  
Vol 19 (2) ◽  
pp. 077
Author(s):  
Ireneusz Haponiuk ◽  
Maciej Chojnicki ◽  
Konrad Paczkowski ◽  
Wojciech Kosiak ◽  
Radosław Jaworski ◽  
...  
Keyword(s):  
Right Ventricle ◽  
Tricuspid Valve ◽  
Mild Hypothermia ◽  
Heart Function ◽  
Thromboembolic Complication ◽  
Surgical Removal ◽  
Unusual Complication ◽  
Type I ◽  
Definitive Therapy ◽  
The Right

The presence of a pathologic mass in the right ventricle (RV) may lead to hemodynamic consequences and to a life-threatening incident of pulmonary embolism. The diagnosis of an unstable thrombus in the right heart chamber usually necessitates intensive treatment to dissolve or remove the pathology. We present a report of an unusual complication of severe ketoacidosis: thrombus in the right ventricle, removed from the tricuspid valve (TV) apparatus. A four-year-old boy was diagnosed with diabetes mellitus (DM) type I de novo. During hospitalization, a 13.9 × 8.4 mm tumor in the RV was found in a routine cardiac ultrasound. The patient was referred for surgical removal of the floating lesion from the RV. The procedure was performed via midline sternotomy with extracorporeal circulation (ECC) and mild hypothermia. Control echocardiography showed complete tumor excision with normal atrioventricular valves and heart function. Surgical removal of the thrombus from the tricuspid valve apparatus was effective, safe, and a definitive therapy for thromboembolic complication of pediatric severe ketoacidosis.<br /><br />

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