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.

Abstract 257: Clonal Analysis Of Multipotent Cardiovascular Progenitors That Generate Cardiomyocytes During Development

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Konstantina Ioanna Sereti ◽  
Paniz Kamran Rashani ◽  
Peng Zhao ◽  
Reza Ardehali
Keyword(s):  
Single Cell ◽  
Heart Development ◽  
Cardiac Development ◽  
Clonal Analysis ◽  
Cardiac Cells ◽  
Single Cell Level ◽  
Reporter System ◽  
Cell Level ◽  
Cardiac Progenitors

It has been proposed that cardiac development in lower vertebrates is driven by the proliferation of cardiomyocytes. Similarly, cycling myocytes have been suggested to direct cardiac regeneration in neonatal mice after injury. Although, the role of cardiomyocyte proliferation in cardiac tissue generation during development has been well documented, the extent of this contribution as well as the role of other cell types, such as progenitor cells, still remains controversial. Here we used a novel stochastic four-color Cre-dependent reporter system (Rainbow) that allows labeling at a single cell level and retrospective analysis of the progeny. Cardiac progenitors expressing Mesp1 or Nkx2.5 were shown to be a source of cardiomyocytes during embryonic development while the onset of αMHC expression marked the developmental stage where the capacity of cardiac cells to proliferate diminishes significantly. Through direct clonal analysis we provide strong evidence supporting that cardiac progenitors, as opposed to mature cardiomyocytes, are the main source of cardiomyocytes during cardiac development. Moreover, we have identified quadri-, tri-, bi, and uni-potent progenitors that at a single cell level can generate cardiomyocytes, fibroblasts, endothelial and smooth muscle cells. Although existing cardiomyocytes undergo limited proliferation, our data indicates that it is mainly the progenitors that contribute to heart development. Furthermore, we show that the limited proliferation capacity of cardiomyocytes observed during normal development was enhanced following neonatal cardiac injury allowing almost complete regeneration of the scared tissue. However, this ability was largely absent in adult injured hearts. Detailed characterization of dividing cardiomyocytes and proliferating progenitors would greatly benefit the development of novel therapeutic options for cardiovascular diseases.

scholarly journals Metabolic reprogramming from glycolysis to amino acid utilization in cardiac HIF1α deficient mice

2019 ◽  
Author(s):  
Ivan Menendez-Montes ◽  
Beatriz Escobar ◽  
Beatriz Palacios ◽  
Manuel J. Gomez ◽  
Elena Bonzon ◽  
...  
Keyword(s):  
Amino Acid ◽  
Heart Development ◽  
Cardiac Development ◽  
Building Blocks ◽  
Embryonic Heart ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Metabolic Switch ◽  
Cardiac Growth ◽  
Cardiac Progenitors

AbstractRationaleHypoxia is an important environmental cue implicated in several physiopathological processes, including heart development. Several mouse models of activation or inhibition of hypoxia have been previously described. While gain of function models have been extensively characterized and indicate that HIF1 signaling needs to be tightly regulated to ensure a proper cardiac development, there is lack of consensus in the field about the functional outcomes of HIF1α loss.ObjectiveIn this study, we aim to assess the consequences of cardiac deletion of HIF1α during heart development and identify the cardiac adaptations to HIF1 loss.Methods and ResultsHere, we used a conditional deletion model ofHif1ain NKX2.5+cardiac progenitors. By a combination of histology, electron microscopy, massive gene expression studies, proteomics, metabolomics and cardiac imaging, we found that HIF1α is dispensable for cardiac development.Hif1aloss results in glycolytic inhibition in the embryonic heart without affecting normal cardiac growth. However, together with a premature increase in mitochondrial number by E12.5, we found global upregulation of amino acid transport and catabolic processes. Interestingly, this amino acid catabolism activation is transient and does not preclude the normal cardiac metabolic switch towards fatty acid oxidation (FAO) after E14.5. Moreover,Hif1aloss is accompanied by an increase in ATF4, described as an important regulator of several amino acid transporters.ConclusionsOur data indicate that HIF1α is not required for normal cardiac development and suggest that additional mechanisms can compensateHif1aloss. Moreover, our results reveal the metabolic flexibility of the embryonic heart at early stages of development, showing the capacity of the myocardium to adapt its energy source to satisfy the energetic and building blocks demands to achieve normal cardiac growth and function. This metabolic reprograming might be relevant in the setting of adult cardiac failure.

scholarly journals From Stripes to a Beating Heart: Early Cardiac Development in Zebrafish

2021 ◽  
Vol 8 (2) ◽  
pp. 17
Author(s):  
Cassie L. Kemmler ◽  
Fréderike W. Riemslagh ◽  
Hannah R. Moran ◽  
Christian Mosimann
Keyword(s):  
Congenital Heart Defects ◽  
Heart Development ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Heart Defects ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Zebrafish Model ◽  
Lateral Plate ◽  
Cardiac Progenitors

The heart is the first functional organ to form during vertebrate development. Congenital heart defects are the most common type of human birth defect, many originating as anomalies in early heart development. The zebrafish model provides an accessible vertebrate system to study early heart morphogenesis and to gain new insights into the mechanisms of congenital disease. Although composed of only two chambers compared with the four-chambered mammalian heart, the zebrafish heart integrates the core processes and cellular lineages central to cardiac development across vertebrates. The rapid, translucent development of zebrafish is amenable to in vivo imaging and genetic lineage tracing techniques, providing versatile tools to study heart field migration and myocardial progenitor addition and differentiation. Combining transgenic reporters with rapid genome engineering via CRISPR-Cas9 allows for functional testing of candidate genes associated with congenital heart defects and the discovery of molecular causes leading to observed phenotypes. Here, we summarize key insights gained through zebrafish studies into the early patterning of uncommitted lateral plate mesoderm into cardiac progenitors and their regulation. We review the central genetic mechanisms, available tools, and approaches for modeling congenital heart anomalies in the zebrafish as a representative vertebrate model.

Abstract 16013: Direct Nkx2-5 Transcriptional Repression of Isl1 Controls Cardiomyocyte Subtype Identity

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Alexander Goedel ◽  
Tatjana Dorn ◽  
Jason T Lam ◽  
Franziska Herrmann ◽  
Jessica Haas ◽  
...  
Keyword(s):  
Heart Development ◽  
Transcriptional Repression ◽  
Embryonic Stem ◽  
Cardiac Differentiation ◽  
Heart Tube ◽  
Cardiac Progenitors ◽  
Gene Enhancer ◽  
Heart Field ◽  
Homeobox Protein ◽  
Islet 1

During heart development the second heart field (SHF) provides progenitor cells for most cardiomyocytes and expresses the LIM-homeodomain transcription factor Islet-1 (Isl1) and the homeobox protein Nkx2-5. Here, we show that a direct repression of Isl1 transcription by Nkx2-5 is necessary for proper specification and maturation of ventricular and atrial chamber-specific myocardial lineages. Overexpression of Nkx2-5 in mouse embryonic stem cells (ESCs) delayed specification of cardiac progenitors and inhibited expression of Isl1 and its downstream targets in the Isl1+ precursor population. These effects were partially rescued by Isl1 overexpression. Embryos deficient for Nkx2-5 in the Isl1+ lineage failed to downregulate Isl1 protein in cardiomyocytes of the heart tube (Figure 1A). We demonstrated that Nkx2-5 directly binds to an Isl1 gene enhancer and represses the transcriptional activity of Isl1. Furthermore, we showed that overexpression of Isl1 does not prevent cardiac differentiation of ESCs and in Xenopus laevis embryos. Instead, Isl1 overexpression in ESCs leads to enhanced specification of cardiac progenitors, earlier cardiac differentiation, and increased number of cardiomyocytes (Figure 1B). Functional and molecular analysis of Isl1-overexpressing cardiomyocytes revealed higher beating frequencies in both ESC-derived contracting areas and Xenopus Isl1-gain-of-function hearts (Figure 1C), which was associated with upregulation of nodal-specific genes and downregulation of transcripts of working myocardium. Our findings provide an Isl1/Nkx2-5-mediated mechanism that coordinately regulates the specification of cardiac progenitors towards the different myocardial lineages and ensures proper acquisition of myocyte subtype-identity (Figure 1D).

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 Author response: The Apelin receptor enhances Nodal/TGFβ signaling to ensure proper cardiac development

2016 ◽  
Author(s):  
Ashish R Deshwar ◽  
Serene C Chng ◽  
Lena Ho ◽  
Bruno Reversade ◽  
Ian C Scott
Keyword(s):  
Cardiac Development ◽  
Author Response ◽  
Tgfβ Signaling ◽  
Apelin Receptor

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.

scholarly journals Abnormal Cardiac Development in the Absence of Heart Glycogen

2004 ◽  
Vol 24 (16) ◽  
pp. 7179-7187 ◽  
Author(s):  
Bartholomew A. Pederson ◽  
Hanying Chen ◽  
Jill M. Schroeder ◽  
Weinian Shou ◽  
Anna A. DePaoli-Roach ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Muscle ◽  
Heart Development ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Glycogen Synthase ◽  
Heart Defects ◽  
Mendelian Inheritance ◽  
And Function ◽  
Impaired Cardiac Function

ABSTRACT Glycogen serves as a repository of glucose in many mammalian tissues. Mice lacking this glucose reserve in muscle, heart, and several other tissues were generated by disruption of the GYS1 gene, which encodes an isoform of glycogen synthase. Crossing mice heterozygous for the GYS1 disruption resulted in a significant underrepresentation of GYS1-null mice in the offspring. Timed matings established that Mendelian inheritance was followed for up to 18.5 days postcoitum (dpc) and that ∼90% of GYS1-null animals died soon after birth due to impaired cardiac function. Defects in cardiac development began between 11.5 and 14.5 dpc. At 18.5 dpc, the hearts were significantly smaller, with reduced ventricular chamber size and enlarged atria. Consistent with impaired cardiac function, edema, pooling of blood, and hemorrhagic liver were seen. Glycogen synthase and glycogen were undetectable in cardiac muscle and skeletal muscle from the surviving null mice, and the hearts showed normal morphology and function. Congenital heart disease is one of the most common birth defects in humans, at up to 1 in 50 live births. The results provide the first direct evidence that the ability to synthesize glycogen in cardiac muscle is critical for normal heart development and hence that its impairment could be a significant contributor to congenital heart defects.

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