scholarly journals Hey2 restricts cardiac progenitor addition to the developing heart

2017 ◽  
Author(s):  
Natalie Gibb ◽  
Savo Lazic ◽  
Ashish R. Deshwar ◽  
Xuefei Yuan ◽  
Michael D. Wilson ◽  
...  
Keyword(s):  
Heart Development ◽  
Heart Defects ◽  
Myocardial Cell ◽  
Cell Number ◽  
Tube Formation ◽  
Heart Tube ◽  
Cardiac Progenitors ◽  
Developing Heart ◽  
Heart Field ◽  
A Cell

ABSTRACTA key event in vertebrate heart development is the timely addition of second heart field (SHF) progenitor cells to the poles of the heart tube. This accretion process must occur to the proper extent to prevent a spectrum of congenital heart defects (CHDs). However, the factors that regulate this critical process are poorly understood. Here we demonstrate that Hey2, a bHLH transcriptional repressor, restricts SHF progenitor accretion to the zebrafish heart. hey2 expression demarcated a distinct domain within the cardiac progenitor population. In the absence of Hey2 function an increase in myocardial cell number and SHF progenitors was observed. We found that Hey2 limited proliferation of SHF-derived cardiomyocytes in a cell-autonomous manner, prior to heart tube formation, and further restricted the developmental window over which SHF progenitors were deployed to the heart. Taken together, our data suggests a role for Hey2 in controlling the proliferative capacity and cardiac contribution of late-differentiating cardiac progenitors.

scholarly journals The Expanding Role for Retinoid Signaling in Heart Development

2008 ◽  
Vol 8 ◽  
pp. 194-211 ◽  
Author(s):  
Loretta L. Hoover ◽  
Elizabeth G. Burton ◽  
Bonnie A. Brooks ◽  
Steven W. Kubalak
Keyword(s):  
Vitamin A ◽  
Heart Development ◽  
Cardiac Development ◽  
Tube Formation ◽  
Conditional Knockout ◽  
Heart Tube ◽  
Developmental Defects ◽  
Retinoid Signaling ◽  
Developing Heart ◽  
Cardiac Lineage

The importance of retinoid signaling during cardiac development has long been appreciated, but recently has become a rapidly expanding field of research. Experiments performed over 50 years ago showed that too much or too little maternal intake of vitamin A proved detrimental for embryos, resulting in a cadre of predictable cardiac developmental defects. Germline and conditional knockout mice have revealed which molecular players in the vitamin A signaling cascade are potentially responsible for regulating specific developmental events, and many of these molecules have been temporally and spatially characterized. It is evident that intact and controlled retinoid signaling is necessary for each stage of cardiac development to proceed normally, including cardiac lineage determination, heart tube formation, looping, epicardium formation, ventricular maturation, chamber and outflow tract septation, and coronary arteriogenesis. This review summarizes many of the significant milestones in this field and particular attention is given to recently uncovered cross-talk between retinoid signaling and other developmentally significant pathways. It is our hope that this review of the role of retinoid signaling during formation, remodeling, and maturation of the developing heart will serve as a tool for future discoveries.

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).

scholarly journals A Role for the Cytoskeleton in Heart Looping

2007 ◽  
Vol 7 ◽  
pp. 280-298 ◽  
Author(s):  
Kersti K. Linask ◽  
Michael VanAuker
Keyword(s):  
Heart Development ◽  
Cell Biology ◽  
Heart Defects ◽  
Heart Tube ◽  
Second Heart Field ◽  
The Past ◽  
Complex Process ◽  
Nonmuscle Myosin Ii ◽  
Heart Looping ◽  
Heart Field

Over the past 10 years, key genes involved in specification of left-right laterality pathways in the embryo have been defined. The read-out for misexpression of laterality genes is usually the direction of heart looping. The question of how dextral looping direction occurred mechanistically and how the heart tube bends remains unknown. It is becoming clear from our experiments and those of others that left-right differences in cell proliferation in the second heart field (anterior heart field) drives the dextral direction. Evidence is accumulating that the cytoskeleton is at the center of laterality, and the bending and rotational forces associated with heart looping. If laterality pathways are modulated upstream, the cytoskeleton, including nonmuscle myosin II (NMHC-II), is altered downstream within the cardiomyocytes, leading to looping abnormalities. The cytoskeleton is associated with important mechanosensing and signaling pathways in cell biology and development. The initiation of blood flow during the looping period and the inherent stresses associated with increasing volumes of blood flowing into the heart may help to potentiate the process. In recent years, the steps involved in this central and complex process of heart development that is the basis of numerous congenital heart defects are being unraveled.

Abstract 44: Interaction Of Osr1 And Tbx5 Is Involved In The Mouse Limb And Heart Development

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Linglin Xie ◽  
Lun Zhou ◽  
Patrick Olson ◽  
Jacy O’Keefe ◽  
Qiang Fu
Keyword(s):  
Upper Limb ◽  
Heart Development ◽  
Heart Defects ◽  
Double Outlet Right Ventricle ◽  
Mouse Embryos ◽  
Cardiac Progenitors ◽  
M Phase ◽  
Mouse Limb ◽  
Heart Field ◽  
Normal Identity

Mutations of TBX5 cause Holt-Oram syndrome (HOS) in human, a disease characterized by upper limb and heart defects. Mouse embryos of Osr1 knockout caused similar heart defects, while the upper limb defects have never been reported. By genetically marking Osr1 expressing cells in mice, using Osr1:CreERT2 , we showed that Osr1 expression cells contribute to the atrial septum progenitors between E8.0 and E11.0, and to the forelimb after E9.0. The expression of Osr1 in the forelimb showed a gradient decreasing pattern from the digit 5 to digit 1. Conditional- Tbx5 haploinsuffiency, using Osr1:CreERT2 , compound with Osr1 haploinsuffiency induced more incidence of atrial septal defects (ASDs) and double outlet right ventricle (DORV). Forty percent of these embryos also had digit defects: the digits are either missing, fused or lack normal identity, which were not observed in mouse embryos of either Osr1 or Tbx5 haploinsuffiency. Detailed study of the cardiac progenitors of the compound haploinsufficinecy for Tbx5 and Osr1 showed decreased proliferation in the posterior second heart field, which was associated with lower number of cells transiting from G2 to M phase and less gene expression of Cdk6 and CyclinD2 . In summary, our study demonstrated that interaction of Osr1 and Tbx5 is involved in the mouse limb and heart development and provides a potential mechanism for HOS.

scholarly journals Endoderm Nitric Oxide Signals to Regulate Nascent Development of Cardiac Progenitors in Chicken Embryos

2020 ◽  
Author(s):  
Devan H. Shah ◽  
Sujoy K. Biswas ◽  
Adrian M. Martin ◽  
Simone Bianco ◽  
Wilfred F. Denetclaw
Keyword(s):  
Nitric Oxide ◽  
Heart Development ◽  
Tube Formation ◽  
Heart Tube ◽  
Signal Molecule ◽  
Cardiac Progenitors ◽  
Field Development ◽  
Physiological Signal ◽  
No Signaling ◽  
Differentiation And Proliferation

AbstractHeart development in the chicken embryo is regulated by a concert of cardiogenic morphogens and signaling molecules, but the physiological signal molecule nitric oxide(NO) has not been studied in the context of heart formation. A dynamic investigation of endoderm NO formation demonstrates for the first time a correlation with the established development events of the cardiac heart fields and heart tube. Manipulation of endoderm NO signaling demonstrate a role of NO signaling in the differentiation and proliferation of cardiac progenitors for heart tube formation and cardiac heart field development. To investigate NO in the proliferation of myocardial cells in the heart tube embryos, a computer vision based artificial intelligence approach is followed to automate the long and tedious job of counting cells in a large image dataset. We document NO as an important signaling molecule in the regulation of nascent embryonic cardiogenesis whose effects on other early cardiogenic morphogens is unknown.

scholarly journals Outflow Tract Formation—Embryonic Origins of Conotruncal Congenital Heart Disease

2021 ◽  
Vol 8 (4) ◽  
pp. 42
Author(s):  
Sonia Stefanovic ◽  
Heather C. Etchevers ◽  
Stéphane Zaffran
Keyword(s):  
Congenital Heart ◽  
Cardiac Development ◽  
Heart Defects ◽  
Dynamic Structure ◽  
Cell Types ◽  
Outflow Tract ◽  
Heart Tube ◽  
Heart Field ◽  
Multiple Cell ◽  
The Many

Anomalies in the cardiac outflow tract (OFT) are among the most frequent congenital heart defects (CHDs). During embryogenesis, the cardiac OFT is a dynamic structure at the arterial pole of the heart. Heart tube elongation occurs by addition of cells from pharyngeal, splanchnic mesoderm to both ends. These progenitor cells, termed the second heart field (SHF), were first identified twenty years ago as essential to the growth of the forming heart tube and major contributors to the OFT. Perturbation of SHF development results in common forms of CHDs, including anomalies of the great arteries. OFT development also depends on paracrine interactions between multiple cell types, including myocardial, endocardial and neural crest lineages. In this publication, dedicated to Professor Andriana Gittenberger-De Groot and her contributions to the field of cardiac development and CHDs, we review some of her pioneering studies of OFT development with particular interest in the diverse origins of the many cell types that contribute to the OFT. We also discuss the clinical implications of selected key findings for our understanding of the etiology of CHDs and particularly OFT malformations.

Cardiac embryogenesis

ESC CardioMed ◽  
2018 ◽  
pp. 33-36
Author(s):  
Robert G. Kelly
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
Congenital Heart ◽  
Heart Defects ◽  
Embryonic Heart ◽  
Heart Tube ◽  
Second Heart Field ◽  
Heart Field ◽  
Cell Niche ◽  
The Right

The embryonic heart forms in anterior lateral splanchnic mesoderm and is derived from Mesp1-expressing progenitor cells. During embryonic folding, the earliest differentiating progenitor cells form the linear heart tube in the ventral midline. The heart tube extends in length and loops to the right as new myocardium is progressively added at the venous and arterial poles from multipotent second heart field cardiovascular progenitor cells in contiguous pharyngeal mesoderm. While the linear heart tube gives rise to the left ventricle, the right ventricle, outflow tract, and a large part of atrial myocardium are derived from the second heart field. Progressive myocardial differentiation is controlled by intercellular signals within the progenitor cell niche. The embryonic heart is the template for septation and growth of the four-chambered definitive heart and defects in progenitor cell deployment result in a spectrum of common forms of congenital heart defects.

scholarly journals Continuous addition of progenitors forms the cardiac ventricle in zebrafish

2017 ◽  
Author(s):  
Anastasia Felker ◽  
Karin D. Prummel ◽  
Anne M. Merks ◽  
Michaela Mickoleit ◽  
Eline C. Brombacher ◽  
...  
Keyword(s):  
Heart Development ◽  
High Speed ◽  
Continuous Process ◽  
Late Phase ◽  
Lineage Tracing ◽  
Heart Tube ◽  
High Speed Imaging ◽  
Lateral Plate ◽  
Cardiac Ventricle ◽  
Heart Field

AbstractThe vertebrate heart develops from several progenitor lineages. After early-differentiating first heart field (FHF) progenitors form the linear heart tube, late-differentiating second heart field (SHF) progenitors extend atrium, ventricle, and form the inflow and outflow tracts (IFT/OFT). However, the position and migration of late-differentiating progenitors during heart formation remains unclear. Here, we tracked zebrafish heart development using transgenics based on the cardiopharyngeal transcription factor gene tbx1. Live-imaging uncovered a tbx1 reporter-expressing cell sheath that from anterior lateral plate mesoderm continuously disseminates towards the forming heart tube. High-speed imaging and optogenetic lineage tracing corroborated that the zebrafish ventricle forms through continuous addition from the undifferentiated progenitor sheath followed by late-phase accrual of the bulbus arteriosus (BA). FGF inhibition during sheath migration reduced ventricle size and abolished BA formation, refining the window of FGF action during OFT formation. Our findings consolidate previous end-point analyses and establish zebrafish ventricle formation as a continuous process.

scholarly journals Ventricular, atrial and outflow tract heart progenitors arise from spatially and molecularly distinct regions of the primitive streak

2020 ◽  
Author(s):  
Kenzo Ivanovitch ◽  
Pablo Soro-Barrio ◽  
Probir Chakravarty ◽  
Rebecca A Jones ◽  
S. Neda Mousavy Gharavy ◽  
...  
Keyword(s):  
Single Cell ◽  
Heart Development ◽  
Primitive Streak ◽  
Outflow Tract ◽  
Lineage Tracing ◽  
Molecular Signature ◽  
Genetic Lineage ◽  
Cardiac Progenitors ◽  
Heart Field ◽  
Genetic Lineage Tracing

AbstractThe heart develops from two sources of mesoderm progenitors, the first and second heart field (FHF and SHF). Using a single cell transcriptomic assay in combination with genetic lineage tracing, we find the FHF and SHF are subdivided into distinct pools of progenitors in gastrulating mouse embryos at earlier stages than previously thought. Each subpopulation has a distinct origin in the primitive streak. The first progenitors to leave the primitive streak contribute to the left ventricle, shortly after right ventricle progenitor emigrate, followed by the outflow tract and atrial progenitors. Although cells allocated to the outflow tract and atrium leave the primitive streak at a similar stage, they arise from different regions. Outflow tract originate from distal locations in the primitive streak while atrial progenitors are positioned more proximally. Moreover, single cell RNA sequencing demonstrates that the primitive streak cells contributing to the ventricles have a distinct molecular signature from those forming the outflow tract and atrium. We conclude that cardiac progenitors are pre-patterned within the primitive streak and this prefigures their allocation to distinct anatomical structures of the heart. Together, our data provide a new molecular and spatial map of mammalian cardiac progenitors that will support future studies of heart development, function and disease.

scholarly journals Ventricular, atrial, and outflow tract heart progenitors arise from spatially and molecularly distinct regions of the primitive streak

PLoS Biology ◽  
2021 ◽  
Vol 19 (5) ◽  
pp. e3001200
Author(s):  
Kenzo Ivanovitch ◽  
Pablo Soro-Barrio ◽  
Probir Chakravarty ◽  
Rebecca A. Jones ◽  
Donald M. Bell ◽  
...  
Keyword(s):  
Single Cell ◽  
Heart Development ◽  
Primitive Streak ◽  
Outflow Tract ◽  
Lineage Tracing ◽  
Molecular Signature ◽  
Genetic Lineage ◽  
Cardiac Progenitors ◽  
Heart Field ◽  
Genetic Lineage Tracing

The heart develops from 2 sources of mesoderm progenitors, the first and second heart field (FHF and SHF). Using a single-cell transcriptomic assay combined with genetic lineage tracing and live imaging, we find the FHF and SHF are subdivided into distinct pools of progenitors in gastrulating mouse embryos at earlier stages than previously thought. Each subpopulation has a distinct origin in the primitive streak. The first progenitors to leave the primitive streak contribute to the left ventricle, shortly after right ventricle progenitor emigrate, followed by the outflow tract and atrial progenitors. Moreover, a subset of atrial progenitors are gradually incorporated in posterior locations of the FHF. Although cells allocated to the outflow tract and atrium leave the primitive streak at a similar stage, they arise from different regions. Outflow tract cells originate from distal locations in the primitive streak while atrial progenitors are positioned more proximally. Moreover, single-cell RNA sequencing demonstrates that the primitive streak cells contributing to the ventricles have a distinct molecular signature from those forming the outflow tract and atrium. We conclude that cardiac progenitors are prepatterned within the primitive streak and this prefigures their allocation to distinct anatomical structures of the heart. Together, our data provide a new molecular and spatial map of mammalian cardiac progenitors that will support future studies of heart development, function, and disease.

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