scholarly journals Myocardial Notch-Rbpj deletion does not affect heart development or function

2018 ◽  
Author(s):  
Alejandro Salguero-Jiménez ◽  
Joaquim Grego-Bessa ◽  
Gaetano D’Amato ◽  
Luis J. Jiménez-Borreguero ◽  
José Luis de la Pompa
Keyword(s):  
Notch Signaling ◽  
Heart Development ◽  
Cardiac Development ◽  
Heart Function ◽  
Physiological Role ◽  
Double Outlet Right Ventricle ◽  
Cardiac Valves ◽  
Myocardial Development ◽  
Normal Expression ◽  
And Function

AbstractDuring vertebrate cardiac development NOTCH signaling activity in the endocardium is essential for the crosstalk between endocardium and myocardium that initiates ventricular trabeculation and valve primordium formation. This crosstalk leads later to the maturation and compaction of the ventricular chambers and the morphogenesis of the cardiac valves, and its alteration may lead to disease. Although endocardial NOTCH signaling has been shown to be crucial for heart development, its physiological role in the myocardium has not been clearly established. Here we have used a genetic strategy to evaluate the role of NOTCH in myocardial development. We have inactivated the unique and ubiquitous NOTCH effector RBPJ in the early cardiomyocytes progenitors, and examined its consequences in cardiac development and function. Our results demonstrate that mice with cTnT-Cre-mediated myocardial-specific deletion of Rbpj develop to term, with homozygous mutant animals showing normal expression of cardiac development markers, and normal adult heart function. Similar observations have been obtained after Notch1 deletion with cTnT-Cre. We have also deleted Rbpj in both myocardial and endocardial progenitor cells, using the Nkx2.5-Cre driver, resulting in ventricular septal defect (VSD), double outlet right ventricle (DORV), and bicuspid aortic valve (BAV), due to NOTCH signaling abrogation in the endocardium of cardiac valves territories. Our data demonstrate that NOTCH-RBPJ inactivation in the myocardium does not affect heart development or adult cardiac function.

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.

The multiple functions of the proepicardial/epicardial cell lineage in heart development

2018 ◽  
Author(s):  
Robert Dettman ◽  
Juan Antonio Guadix ◽  
Elena Cano ◽  
Rita Carmona ◽  
Ramón Muñoz-Chápuli
Keyword(s):  
Heart Development ◽  
Epithelial Mesenchymal Transition ◽  
Cardiac Development ◽  
Cell Layer ◽  
Cell Lineage ◽  
Outer Cell ◽  
Mesenchymal Transition ◽  
Myocardial Development ◽  
Epicardial Cell ◽  
Outer Cell Layer

The epicardium is the outer cell layer of the vertebrate heart. In recent years, both the embryonic and adult epicardium have revealed unsuspected peculiarities and functions, which are essential for cardiac development. In this chapter we review the current literature on the epicardium, and describe its evolutionary origin, the mechanisms leading to the induction of its extracardiac progenitor tissue, the proepicardium, and the way in which the proepicardium is transferred to the heart to form the epicardium. We also describe the epicardial epithelial–mesenchymal transition from which mesenchymal cells originate, and the developmental fate of these cells, which contribute to the vascular, interstitial, valvular, and adipose tissue. Finally, we review the molecular interactions established between the epicardium and the myocardium, which are key for myocardial development and can also play a role in cardiac homeostasis. This chapter highlights how the epicardium has become a major protagonist in cardiac biology.

Mutations in CHMP4C cause dilated cardiomyopathy via dysregulation of autophagy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
N.W Zhou ◽  
L Tang ◽  
Y.Y Jiang ◽  
X.J Li ◽  
W.P Zhao ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Heart Development ◽  
Cardiac Development ◽  
Heart Function ◽  
Critical Role ◽  
Genetic Diagnosis ◽  
Gene Mutations ◽  
Clinical Genetic ◽  
Whole Exome

Abstract Background Gene mutations have been implicated in DCM. However, due to the difficulty of clinical genetic diagnosis, more causal genes potentially related to DCM remain to be discovered. Methods We screened for gene mutations in more than 400 cases from families with hereditary cardiovascular disease using whole-exome sequencing. Then we validated biological functions of CHMP4C mutations in zebrafish models. To further assess the mechanism of CHMP4C mutations, we evaluated the potential signaling pathway in the cells. Results We identification of CHMP4C variants that segregated with DCM variants in four families from a total of 411 families via whole-exome sequencing. We further validate the function of CHMP4C in heart function in zebrafish models and found that over-expression of CHMP4C variants in zebrafish resulted in cardiac malformation, pericardial edema and increased heart rate, consistent with CHMP4C mutation-associated findings in DCM patients. Furthermore, we found that mutations in CHMP4C impaired autophagy and activated apoptosis in HEK293T cells, suggesting that the molecular mechanism of CHMP4C is involved in heart development. Conclusions CHMP4C is a novel candidate gene for DCM and may play a critical role in cardiac development by regulating autophagy. Funding Acknowledgement Type of funding source: None

scholarly journals miR-128a Acts as a Regulator in Cardiac Development by Modulating Differentiation of Cardiac Progenitor Cell Populations

2020 ◽  
Vol 21 (3) ◽  
pp. 1158 ◽  
Author(s):  
Sarah C. Hoelscher ◽  
Theresia Stich ◽  
Anne Diehm ◽  
Harald Lahm ◽  
Martina Dreßen ◽  
...  
Keyword(s):  
Pluripotent Stem Cells ◽  
Heart Development ◽  
Regulatory Networks ◽  
Progenitor Cell ◽  
Cardiac Development ◽  
Loss Of Function ◽  
And Function ◽  
Cardiac Transcription Factors ◽  
Beating Frequency

MicroRNAs (miRs) appear to be major, yet poorly understood players in regulatory networks guiding cardiogenesis. We sought to identify miRs with unknown functions during cardiogenesis analyzing the miR-profile of multipotent Nkx2.5 enhancer cardiac progenitor cells (NkxCE-CPCs). Besides well-known candidates such as miR-1, we found about 40 miRs that were highly enriched in NkxCE-CPCs, four of which were chosen for further analysis. Knockdown in zebrafish revealed that only miR-128a affected cardiac development and function robustly. For a detailed analysis, loss-of-function and gain-of-function experiments were performed during in vitro differentiations of transgenic murine pluripotent stem cells. MiR-128a knockdown (1) increased Isl1, Sfrp5, and Hcn4 (cardiac transcription factors) but reduced Irx4 at the onset of cardiogenesis, (2) upregulated Isl1-positive CPCs, whereas NkxCE-positive CPCs were downregulated, and (3) increased the expression of the ventricular cardiomyocyte marker Myl2 accompanied by a reduced beating frequency of early cardiomyocytes. Overexpression of miR-128a (4) diminished the expression of Isl1, Sfrp5, Nkx2.5, and Mef2c, but increased Irx4, (5) enhanced NkxCE-positive CPCs, and (6) favored nodal-like cardiomyocytes (Tnnt2+, Myh6+, Shox2+) accompanied by increased beating frequencies. In summary, we demonstrated that miR-128a plays a so-far unknown role in early heart development by affecting the timing of CPC differentiation into various cardiomyocyte subtypes.

scholarly journals Tet inactivation disrupts YY1 binding and long-range chromatin interactions during embryonic heart development

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Shaohai Fang ◽  
Jia Li ◽  
Yang Xiao ◽  
Minjung Lee ◽  
Lei Guo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Heart Development ◽  
Cardiac Development ◽  
Physiological Role ◽  
Chromatin Accessibility ◽  
Dna Demethylation ◽  
Chromatin Organization ◽  
Cardiac Tissues ◽  
Transcriptional Reprogramming ◽  
Chromatin Interactions

Abstract Tet-mediated DNA demethylation plays an important role in shaping the epigenetic landscape and chromatin accessibility to control gene expression. While several studies demonstrated pivotal roles of Tet in regulating embryonic development, little is known about their functions in heart development. Here we analyze DNA methylation and hydroxymethylation dynamics during early cardiac development in both human and mice. We find that cardiac-specific deletion of Tet2 and Tet3 in mice (Tet2/3-DKO) leads to ventricular non-compaction cardiomyopathy (NCC) with embryonic lethality. Single-cell RNA-seq analyses reveal a reduction in cardiomyocyte numbers and transcriptional reprogramming in cardiac tissues upon Tet2/3 depletion. Impaired DNA demethylation and reduced chromatin accessibility in Tet2/3-DKO mice further compromised Ying-yang1 (YY1) binding to its genomic targets, and perturbed high-order chromatin organization at key genes involved in heart development. Our studies provide evidence of the physiological role of Tet in regulating DNA methylation dynamics and chromatin organization during early heart development.

scholarly journals Origin, Fate, and Function of Epicardium-Derived Cells (EPDCs) in Normal and Abnormal Cardiac Development

2007 ◽  
Vol 7 ◽  
pp. 1777-1798 ◽  
Author(s):  
Heleen Lie-Venema ◽  
Nynke M. S. van den Akker ◽  
Noortje A. M. Bax ◽  
Elizabeth M. Winter ◽  
Saskia Maas ◽  
...  
Keyword(s):  
Heart Development ◽  
Cardiac Development ◽  
Clinical Importance ◽  
Fiber Formation ◽  
Developmental Defect ◽  
Heart Tube ◽  
Atrioventricular Cushions ◽  
Mesenchymal Transformation ◽  
And Function ◽  
Myocardial Architecture

During heart development, cells of the primary and secondary heart field give rise to the myocardial component of the heart. The neural crest and epicardium provide the heart with a considerable amount of nonmyocardial cells that are indispensable for correct heart development. During the past 2 decades, the importance of epicardium-derived cells (EPDCs) in heart formation became increasingly clear. The epicardium is embryologically formed by the outgrowth of proepicardial cells over the naked heart tube. Following epithelial-mesenchymal transformation, EPDCs form the subepicardial mesenchyme and subsequently migrate into the myocardium, and differentiate into smooth muscle cells and fibroblasts. They contribute to the media of the coronary arteries, to the atrioventricular valves, and the fibrous heart skeleton. Furthermore, they are important for the myocardial architecture of the ventricular walls and for the induction of Purkinje fiber formation.Whereas the exact signaling cascades in EPDC migration and function still need to be elucidated, recent research has revealed several factors that are involved in EPDC migration and specialization, and in the cross-talk between EPDCs and other cells during heart development. Among these factors are the Ets transcription factors Ets-1 and Ets-2. New data obtained with lentiviral antisense constructs targeting Ets-1 and Ets-2 specifically in the epicardium indicate that both factors are independently involved in the migratory behavior of EPDCs. Ets-2 seems to be especially important for the migration of EPDCs into the myocardial wall, and to subendocardial positions in the atrioventricular cushions and the trabeculae.With respect to the clinical importance of correct EPDC development, the relation with coronary arteriogenesis has been noted well before. In this review, we also propose a role for EPDCs in cardiac looping, and emphasize their contribution to the development of the valves and myocardial architecture. Lastly, we focus on the congenital heart anomalies that might be caused primarily by an epicardial developmental defect.

scholarly journals Effects of miR-155 on High Glucose Induced-Cardiac Developmental Defects of Zebrafish Embryos

2020 ◽  
Author(s):  
Kai Zhang ◽  
Yijian Zhang ◽  
Mengyuan Huang ◽  
Xiangjiang Yuan ◽  
Liyuan Wei ◽  
...  
Keyword(s):  
High Glucose ◽  
Heart Development ◽  
Structural Changes ◽  
Cardiac Development ◽  
Heart Function ◽  
Maternal Serum ◽  
Teratogenic Effect ◽  
Zebrafish Embryos ◽  
Cell Stage ◽  
Developmental Defects

Abstract Background: Gestational diabetes mellitus (GDM) is known to have a teratogenic effect on heart development. However, the underlying mechanisms are still unclear. Former studies determined that miR-155 is elevated in GDM patients. Besides, miR-155 is a key molecule for development. In the present study, we explored the potential role of miR-155 in heart development and the effect of miR-155 on high glucose-induced cardiac developmental defects.Methods: Zebrafish embryos were exposed to 2% D-Glucose in a fluctuating manner. Activators or inhibitors of miR-155, Ets1, and Igf1 were injected into one-cell stage embryos. The expression levels of miR-155, Ets1 and cardiac specific genes were evaluated by real-time PCR. The regulation of Igf1 by Ets1 was examined using luciferase assays. The levels of reactive oxygen species (ROS) were analyzed by DCFH-DA. Proteins involved in Igf1 pathway were detected by western blot analysis. Maternal serum miR-155 was determined using ELISA. Fetal cardiac structural and functional characteristics in diabetic or healthy pregnancies were performed by echocardiography.Results: miR-155 levels are increased in serum from GDM patients and are correlated with fetal cardiac structural changes. High glucose exposure in zebrafish embryos altered the morphology of the heart, impaired the heart function, and increased the expression of miR-155 as well as cardiac specific genes. Upregulation of miR-155 activated Igf1-Akt-Gsk3β pathway by targeting Ets1 and increased the production of ROS and may thereby exert teratogenic effect on cardiac development. In addition, knockdown of miR-155 blocked Igf1 survival pathway and induced apoptosis and may thus induced zebrafish cardiac developmental defects.Conclusion: miR-155 is a key molecule for heart development and is involved in high glucose-induced cardiac malformation, and it might be a novel biomarker as well as a potential drug target of high glucose-induced cardiac defects.

scholarly journals The Role of Tbx20 in Cardiovascular Development and Function

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuwen Chen ◽  
Deyong Xiao ◽  
Lu Zhang ◽  
Chen-Leng Cai ◽  
Bai-Yan Li ◽  
...  
Keyword(s):  
Cardiac Development ◽  
Heart Function ◽  
Heart Defects ◽  
Transcriptional Networks ◽  
Complex Spectrum ◽  
Cardiovascular Development ◽  
T Box ◽  
Heart Arrhythmia ◽  
And Function

Tbx20 is a member of the Tbx1 subfamily of T-box-containing genes and is known to play a variety of fundamental roles in cardiovascular development and homeostasis as well as cardiac remodeling in response to pathophysiological stresses. Mutations in TBX20 are widely associated with the complex spectrum of congenital heart defects (CHDs) in humans, which includes defects in chamber septation, chamber growth, and valvulogenesis. In addition, genetic variants of TBX20 have been found to be associated with dilated cardiomyopathy and heart arrhythmia. This broad spectrum of cardiac morphogenetic and functional defects is likely due to its broad expression pattern in multiple cardiogenic cell lineages and its critical regulation of transcriptional networks during cardiac development. In this review, we summarize recent findings in our general understanding of the role of Tbx20 in regulating several important aspects of cardiac development and homeostasis and heart function.

scholarly journals Integration of multiple imaging platforms to uncover cardiac defects in adult zebrafish

2020 ◽  
Author(s):  
Anabela Bensimon-Brito ◽  
Giulia L. M. Boezio ◽  
João Cardeira-da-Silva ◽  
Astrid Wietelmann ◽  
Christian S. M. Helker ◽  
...  
Keyword(s):  
Cardiac Development ◽  
Genetic Model ◽  
Heart Function ◽  
Imaging Techniques ◽  
Adult Zebrafish ◽  
Micro Computed Tomography ◽  
Cardiac Defects ◽  
Multiple Parameters ◽  
Multiple Imaging ◽  
And Function

AbstractMammalian models have been instrumental to investigate adult heart function and human disease. However, electrophysiological differences with human hearts and high costs emphasize the need for additional models. The zebrafish is a well-established genetic model to study cardiac development and function; however, analysis of cardiac phenotypes in adult specimens is particularly challenging as they are opaque. Here, we optimized and combined multiple imaging techniques including echocardiography, magnetic resonance imaging and micro-computed tomography to identify and analyze cardiac phenotypes in adult zebrafish. Using alk5a/tgfbr1a mutants as a case study, we observed morphological and functional cardiac defects, which were undetected with conventional approaches. Correlation analysis of multiple parameters revealed an association between hemodynamic defects and structural alterations of the heart, as observed clinically. Thus, we report a comprehensive and sensitive platform to identify otherwise indiscernible cardiac phenotypes in adult zebrafish, a model with clear advantages to study cardiac function and disease.

scholarly journals The ECM as a driver of heart development and repair

Development ◽  
2021 ◽  
Vol 148 (5) ◽  
pp. dev191320
Author(s):  
Christopher J. Derrick ◽  
Emily S. Noël
Keyword(s):  
Extracellular Matrix ◽  
Heart Development ◽  
Cardiac Development ◽  
Cardiac Cells ◽  
Heart Regeneration ◽  
Heart Morphogenesis ◽  
Developing Heart ◽  
Spatiotemporal Changes ◽  
And Function

ABSTRACTThe developing heart is formed of two tissue layers separated by an extracellular matrix (ECM) that provides chemical and physical signals to cardiac cells. While deposition of specific ECM components creates matrix diversity, the cardiac ECM is also dynamic, with modification and degradation playing important roles in ECM maturation and function. In this Review, we discuss the spatiotemporal changes in ECM composition during cardiac development that support distinct aspects of heart morphogenesis. We highlight conserved requirements for specific ECM components in human cardiac development, and discuss emerging evidence of a central role for the ECM in promoting heart regeneration.

Sign in / Sign up

Export Citation Format

Share Document