scholarly journals Understanding inter-tissue crosstalk during zebrafish cardiovascular development

2021 ◽  
Author(s):  
◽  
Giulia L. M. Boezio
Keyword(s):  
Heart Development ◽  
Cardiovascular Development ◽  
Paracrine Signalling ◽  
Myocardial Wall ◽  
Endothelial Proliferation ◽  
Cell Organization ◽  
Epicardial Layer ◽  
Multicellular Interactions ◽  
Intercellular Communications ◽  
Pharmacological Manipulations

My PhD work employed genetic and pharmacological manipulations, coupled with highresolution live imaging, to understand intercellular communications during zebrafish cardiovascular development. The heart is the first organ to form, and it is composed of several tissues, among which interactions are crucial. I identified two important interactions between muscular and non-muscular tissues in poorly characterized contexts, and the molecules required for the signalling. First, I discovered an important cellular and molecular crosstalk orchestrating the development of the cardiac outflow tract (i.e., the aortic root in mammals). Endothelial-derived TGF-beta signalling controls the generation of the local extracellular matrix (ECM). The ECM in turn affects endothelial proliferation as well as smooth muscle cell organization (Boezio et al, 2020; Bensimon-Brito*, Boezio* et al, 2020). In my second project, I investigated the crosstalk between the epicardial layer and the myocardial wall. By generating epicardial-impairment models, I identified a novel role for the epicardium in regulating cardiomyocyte volume during heart development (Boezio et al, 2021). Ultimately, this research contributed to our understanding of how paracrine signalling controls the multicellular interactions integral to organogenesis.

Embryonic development of the heart

Development ◽  
1969 ◽  
Vol 22 (3) ◽  
pp. 333-348
Author(s):  
Francis J. Manasek
Keyword(s):  
Cell Layer ◽  
Embryonic Heart ◽  
Outer Cell ◽  
Chick Embryos ◽  
Myocardial Wall ◽  
Undifferentiated Cells ◽  
Epicardial Layer ◽  
Outer Cell Layer ◽  
Heart Wall

The mature heart may be thought of as consisting of three layers, endocardium, myocardium, and an outer investing tissue called the epicardium. During early formation of the tubular heart of chick embryos, at about the 8-somite stage, two tissue layers become clearly discernible with the light microscope: the endocardium and the developing myocardial wall. The outer epicardial layer does not appear until later in development. It is generally accepted that embryonic heart wall or ‘epimyocardium’ is composed of muscle and undifferentiated cells. As its name implies, the epimyocardium is thought to give rise to myocardium and epicardium. Kurkiewicz (1909) suggested that the epicardium was not an epimyocardial derivative but rather is formed from cells originating in the sinus venosus region, which migrate over the surface of the heart. Nevertheless, it has become generally accepted that the outer cell layer of the embryonic heart wall differentiates in situ to give rise to the definitive visceral epicardium (Patten, 1953).

scholarly journals The flow responsive transcription factor Klf2 is required for myocardial wall integrity by modulating Fgf signaling

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Seyed Javad Rasouli ◽  
Mohamed El-Brolosy ◽  
Ayele Taddese Tsedeke ◽  
Anabela Bensimon-Brito ◽  
Parisa Ghanbari ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cardiac Contractility ◽  
Cardiovascular Development ◽  
Fgf Signaling ◽  
Wild Type ◽  
Complex Interplay ◽  
Exact Role ◽  
Cardiac Tissues ◽  
Myocardial Wall ◽  
Apical Side

Complex interplay between cardiac tissues is crucial for their integrity. The flow responsive transcription factor KLF2, which is expressed in the endocardium, is vital for cardiovascular development but its exact role remains to be defined. To this end, we mutated both klf2 paralogues in zebrafish, and while single mutants exhibit no obvious phenotype, double mutants display a novel phenotype of cardiomyocyte extrusion towards the abluminal side. This extrusion requires cardiac contractility and correlates with the mislocalization of N-cadherin from the lateral to the apical side of cardiomyocytes. Transgenic rescue data show that klf2 expression in endothelium, but not myocardium, prevents this cardiomyocyte extrusion phenotype. Transcriptome analysis of klf2 mutant hearts reveals that Fgf signaling is affected, and accordingly, we find that inhibition of Fgf signaling in wild-type animals can lead to abluminal cardiomyocyte extrusion. These studies provide new insights into how Klf2 regulates cardiovascular development and specifically myocardial wall integrity.

Abstract 052: Epicardial-derived Adrenomedullin Drives Cardiac Hyperplasia During Embryogenesis

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Sarah E Wetzel-Strong ◽  
Manyu Li ◽  
Toshio Nishikimi ◽  
Kathleen M Caron
Keyword(s):  
Embryonic Development ◽  
Heart Development ◽  
Cardiac Development ◽  
Lymphatic Vessels ◽  
Heart Weight ◽  
Cardiovascular Development ◽  
Proliferating Cells ◽  
Over Expression ◽  
Knockout Animals

The multi-functional peptide adrenomedullin ( Adm = gene, AM = protein) plays important roles in embryonic development and disease. Previous studies demonstrated that Adm knockout mice die at embryonic day 13.5 with small, disorganized hearts and hypoplastic lymphatic vessels, highlighting the importance of this peptide in normal cardiovascular development. Since Adm knockout animals are embryonic lethal, our goal was to generate and characterize a novel model of Adm over-expression to study the role of Adm during development and disease processes. Through gene targeting techniques, we generated a novel mouse model of Adm over-expression, abbreviated as Adm hi/hi . When we assessed gene expression of Adm from 10 different tissues, we found Adm hi/hi mice express 3- to 15-fold more Adm than wildtype littermates. Additionally, peptide levels of AM in lung and kidney, as well as circulating plasma levels of AM were elevated 3-fold over wildtype mice, indicating a functional increase in AM. Our initial analysis revealed that adult Adm hi/hi mice have larger heart weight to body weight ratios than wildtype littermates (4.93±0.23 vs. 5.96±0.29, n = 11-12). We found that compared to wildtype, Adm hi/hi embryos have more proliferating cells during heart development (14.46±1.11 vs. 31.97±2.84, n=4), indicating that hyperplasia drives Adm hi/hi heart enlargement. By crossing the Adm hi/hi line to different tissue-specific Cre lines, we were able to excise the stabilizing bovine growth hormone 3’UTR, thereby returning Adm expression levels back to wildtype in cells with active Cre recombinase. Using this approach, we identified the epicardium as a major source of AM during cardiac development. In conclusion, we found that AM derived primarily from the epicardium drives cardiac hyperplasia during embryonic development resulting in persistent, enlarged hearts of adult Adm hi/hi mice. Since our Adm hi/hi mice recapitulate the 3-fold plasma elevation of AM observed during human disease, this mouse line will be a useful tool for studying the role of elevated AM during disease.

Epigenetics and post-transcriptional regulation of cardiovascular development

2018 ◽  
Author(s):  
Jin Yang ◽  
Pei Han ◽  
Wei Li ◽  
Ching-Pin Chang
Keyword(s):  
Heart Development ◽  
Genetic Information ◽  
Cardiovascular Development ◽  
Control Of Gene Expression ◽  
Correct Sequence ◽  
Non Coding Rnas ◽  
Combinatorial Interactions ◽  
Post Transcriptional Regulation ◽  
Rna Complexes ◽  
Developmental Windows

Cardiac organogenesis requires the control of gene expression at distinct developmental windows in order to organize morphogenetic steps in the correct sequence for heart development. This is facilitated by concerted regulation at three levels: chromatin, transcription, and post-transcriptional modifications. Epigenetic regulation at the chromatin level changes the chromatin scaffold of DNA to regulate accessibility of the DNA sequence to transcription factors for genetic activation or repression. At the genome, long non-coding RNAs work with epigenetic factors to alter the chromatin scaffold or form DNA-RNA complexes at specific genomic loci to control the transcription of genetic information. After RNA transcription, the expression of genetic information can be further modified by microRNAs. Each layer of gene regulation requires the participation of many factors, with their combinatorial interactions providing variations of genetic expression at distinct pathophysiological phases of the heart. The major functions of chromatin remodellers and non-coding RNAs are discussed.

scholarly journals Vegfaa instructs cardiac muscle hyperplasia in adult zebrafish

2018 ◽  
Vol 115 (35) ◽  
pp. 8805-8810 ◽  
Author(s):  
Ravi Karra ◽  
Matthew J. Foglia ◽  
Wen-Yee Choi ◽  
Christine Belliveau ◽  
Paige DeBenedittis ◽  
...  
Keyword(s):  
Heart Development ◽  
Epithelial To Mesenchymal Transition ◽  
Cardiac Injury ◽  
Angiogenic Factor ◽  
Regulatory Sequences ◽  
Mesenchymal Transition ◽  
Epicardial Cells ◽  
Myocardial Wall ◽  
Tightly Coupled ◽  
Spatiotemporal Control

During heart development and regeneration, coronary vascularization is tightly coupled with cardiac growth. Although inhibiting vascularization causes defects in the innate regenerative response of zebrafish to heart injury, angiogenic signals are not known to be sufficient for triggering regeneration events. Here, by using a transgenic reporter strain, we found that regulatory sequences of the angiogenic factor vegfaa are active in epicardial cells of uninjured animals, as well as in epicardial and endocardial tissue adjacent to regenerating muscle upon injury. Additionally, we find that induced cardiac overexpression of vegfaa in zebrafish results in overt hyperplastic thickening of the myocardial wall, accompanied by indicators of angiogenesis, epithelial-to-mesenchymal transition, and cardiomyocyte regeneration programs. Unexpectedly, vegfaa overexpression in the context of cardiac injury enabled ectopic cardiomyogenesis but inhibited regeneration at the site of the injury. Our findings identify Vegfa as one of a select few known factors sufficient to activate adult cardiomyogenesis, while also illustrating how instructive factors for heart regeneration require spatiotemporal control for efficacy.

scholarly journals On Zebrafish Disease Models and Matters of the Heart

Biomedicines ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 15 ◽  
Author(s):  
Panagiota Giardoglou ◽  
Dimitris Beis
Keyword(s):  
Heart Development ◽  
Large Scale ◽  
Complex Disease ◽  
Genetic Manipulation ◽  
Association Studies ◽  
Population Analysis ◽  
Genome Wide Association Studies ◽  
Cardiovascular Development ◽  
Regulatory Pathways ◽  
Functional Genomic Analysis

Coronary artery disease (CAD) is the leading form of cardiovascular disease (CVD), which is the primary cause of mortality worldwide. It is a complex disease with genetic and environmental risk factor contributions. Reports in human and mammalian models elucidate age-associated changes in cardiac function. The diverse mechanisms involved in cardiac diseases remain at the center of the research interest to identify novel strategies for prevention and therapy. Zebrafish (Danio rerio) have emerged as a valuable vertebrate model to study cardiovascular development over the last few decades. The facile genetic manipulation via forward and reverse genetic approaches combined with noninvasive, high-resolution imaging and phenotype-based screening has provided new insights to molecular pathways that orchestrate cardiac development. Zebrafish can recapitulate human cardiac pathophysiology due to gene and regulatory pathways conservation, similar heart rate and cardiac morphology and function. Thus, generations of zebrafish models utilize the functional analysis of genes involved in CAD, which are derived from large-scale human population analysis. Here, we highlight recent studies conducted on cardiovascular research focusing on the benefits of the combination of genome-wide association studies (GWAS) with functional genomic analysis in zebrafish. We further summarize the knowledge obtained from zebrafish studies that have demonstrated the architecture of the fundamental mechanisms underlying heart development, homeostasis and regeneration at the cellular and molecular levels.

scholarly journals Desmoglein 2 regulates cardiogenesis by restricting hematopoiesis in the developing murine heart

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hoda Moazzen ◽  
Kateryna Venger ◽  
Sebastian Kant ◽  
Rudolf E. Leube ◽  
Claudia A. Krusche
Keyword(s):  
Heart Development ◽  
Type A ◽  
Regulatory Role ◽  
Structural Defects ◽  
Intercellular Signaling ◽  
Type B ◽  
Cell Clusters ◽  
Cardiac Wall ◽  
Myocardial Wall

AbstractCardiac morphogenesis relies on intricate intercellular signaling. Altered signaling impacts cardiac function and is detrimental to embryonic survival. Here we report an unexpected regulatory role of the desmosomal cell adhesion molecule desmoglein 2 (Dsg2) on murine heart development. A large percentage of Dsg2-mutant embryos develop pericardial hemorrhage. Lethal myocardial rupture is occasionally observed, which is not associated with loss of cardiomyocyte contact but with expansion of abnormal, non-myocyte cell clusters within the myocardial wall. Two types of abnormal cell clusters can be distinguished: Type A clusters involve endocard-associated, round-shaped CD31+ cells, which proliferate and invade the myocardium. They acquire Runx1- and CD44-positivity indicating a shift towards a hematopoietic phenotype. Type B clusters expand subepicardially and next to type A clusters. They consist primarily of Ter119+ erythroid cells with interspersed Runx1+/CD44+ cells suggesting that they originate from type A cell clusters. The observed pericardial hemorrhage is caused by migration of erythrocytes from type B clusters through the epicardium and rupture of the altered cardiac wall. Finally, evidence is presented that structural defects of Dsg2-depleted cardiomyocytes are primary to the observed pathogenesis. We propose that cardiomyocyte-driven paracrine signaling, which likely involves Notch1, directs subsequent trans-differentiation of endo- and epicardial cells. Together, our observations uncover a hitherto unknown regulatory role of Dsg2 in cardiogenesis.

scholarly journals Heart Development, Coronary Vascularization and Ventricular Maturation in a Giant Danio (Devario malabaricus)

2018 ◽  
Vol 6 (3) ◽  
pp. 19 ◽  
Author(s):  
Olubusola Shifatu ◽  
Sarah Glasshagel-Chilson ◽  
Hannah Nelson ◽  
Purva Patel ◽  
Wendy Tomamichel ◽  
...  
Keyword(s):  
Heart Development ◽  
Cardiac Development ◽  
Coronary Vessels ◽  
Environmental Parameters ◽  
Heart Regeneration ◽  
Cardiovascular Development ◽  
Coronary Vasculature ◽  
Physiological Processes ◽  
Giant Danio ◽  
Comprehensive Study

Giant danios (genus Devario), like zebrafish, are teleosts belonging to the danioninae subfamily of cyprinids. Adult giant danios are used in a variety of investigations aimed at understanding cellular and physiological processes, including heart regeneration. Despite their importance, little is known about development and growth in giant danios, or their cardiac and coronary vessels development. To address this scarcity of knowledge, we performed a systematic study of a giant danio (Devario malabaricus), focusing on its cardiac development, from the segmentation period to ten months post-fertilization. Using light and scanning electron microscopy, we documented that its cardiovascular development and maturation proceed along well defined dynamic and conserved morphogenic patterns. The overall size and cardiovascular expansion of this species was significantly impacted by environmental parameters such as rearing densities. The coronary vasculature began to emerge in the late larval stage. More importantly, we documented two possible loci of initiation of the coronary vasculature in this species, and compared the emergence of the coronaries to that of zebrafish and gourami. This is the first comprehensive study of the cardiac growth in a Devario species, and our findings serve as an important reference for further investigations of cardiac biology using this species.

scholarly journals Antenatal Steroids and the IUGR Fetus: Are Exposure and Physiological Effects on the Lung and Cardiovascular System the Same as in Normally Grown Fetuses?

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Janna L. Morrison ◽  
Kimberley J. Botting ◽  
Poh Seng Soo ◽  
Erin V. McGillick ◽  
Jennifer Hiscock ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Development ◽  
Preterm Labour ◽  
Lung Surfactant ◽  
Fetal Lung ◽  
Surfactant Protein ◽  
Cardiovascular Development ◽  
Antenatal Steroids ◽  
Conflicting Evidence ◽  
Increased Risk

Glucocorticoids are administered to pregnant women at risk of preterm labour to promote fetal lung surfactant maturation. Intrauterine growth restriction (IUGR) is associated with an increased risk of preterm labour. Hence, IUGR babies may be exposed to antenatal glucocorticoids. The ability of the placenta or blood brain barrier to remove glucocorticoids from the fetal compartment or the brain is compromised in the IUGR fetus, which may have implications for lung, brain, and heart development. There is conflicting evidence on the effect of exogenous glucocorticoids on surfactant protein expression in different animal models of IUGR. Furthermore, the IUGR fetus undergoes significant cardiovascular adaptations, including altered blood pressure regulation, which is in conflict with glucocorticoid-induced alterations in blood pressure and flow. Hence, antenatal glucocorticoid therapy in the IUGR fetus may compromise regulation of cardiovascular development. The role of cortisol in cardiomyocyte development is not clear with conflicting evidence in different species and models of IUGR. Further studies are required to study the effects of antenatal glucocorticoids on lung, brain, and heart development in the IUGR fetus. Of specific interest are the aetiology of IUGR and the resultant degree, duration, and severity of hypoxemia.

scholarly journals A Missense Mutation in the KLF7 Gene Is a Potential Candidate Variant for Congenital Deafness in Australian Stumpy Tail Cattle Dogs

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 467
Author(s):  
Fangzheng Xu ◽  
Shuwen Shan ◽  
Susan Sommerlad ◽  
Jennifer M. Seddon ◽  
Bertram Brenig
Keyword(s):  
Candidate Gene ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Heart Development ◽  
Genome Wide Association Study ◽  
Whole Genome ◽  
Potential Candidate ◽  
Congenital Deafness ◽  
Cardiovascular Development ◽  
A Genome

Congenital deafness is prevalent among modern dog breeds, including Australian Stumpy Tail Cattle Dogs (ASCD). However, in ASCD, no causative gene has been identified so far. Therefore, we performed a genome-wide association study (GWAS) and whole genome sequencing (WGS) of affected and normal individuals. For GWAS, 3 bilateral deaf ASCDs, 43 herding dogs, and one unaffected ASCD were used, resulting in 13 significantly associated loci on 6 chromosomes, i.e., CFA3, 8, 17, 23, 28, and 37. CFA37 harbored a region with the most significant association (−log10(9.54 × 10−21) = 20.02) as well as 7 of the 13 associated loci. For whole genome sequencing, the same three affected ASCDs and one unaffected ASCD were used. The WGS data were compared with 722 canine controls and filtered for protein coding and non-synonymous variants, resulting in four missense variants present only in the affected dogs. Using effect prediction tools, two variants remained with predicted deleterious effects within the Heart development protein with EGF like domains 1 (HEG1) gene (NC_006615.3: g.28028412G>C; XP_022269716.1: p.His531Asp) and Kruppel-like factor 7 (KLF7) gene (NC_006619.3: g.15562684G>A; XP_022270984.1: p.Leu173Phe). Due to its function as a regulator in heart and vessel formation and cardiovascular development, HEG1 was excluded as a candidate gene. On the other hand, KLF7 plays a crucial role in the nervous system, is expressed in the otic placode, and is reported to be involved in inner ear development. 55 additional ASCD samples (28 deaf and 27 normal hearing dogs) were genotyped for the KLF7 variant, and the variant remained significantly associated with deafness in ASCD (p = 0.014). Furthermore, 24 dogs with heterozygous or homozygous mutations were detected, including 18 deaf dogs. The penetrance was calculated to be 0.75, which is in agreement with previous reports. In conclusion, KLF7 is a promising candidate gene causative for ASCD deafness.

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