Conotruncal myocardium arises from a secondary heart field

The primary heart tube is an endocardial tube, ensheathed by myocardial cells, that develops from bilateral primary heart fields located in the lateral plate mesoderm. Earlier mapping studies of the heart fields performed in whole embryo cultures indicate that all of the myocardium of the developed heart originates from the primary heart fields. In contrast, marking experiments in ovo suggest that the atrioventricular canal, atria and conotruncus are added secondarily to the straight heart tube during looping. The results we present resolve this issue by showing that the heart tube elongates during looping, concomitant with accretion of new myocardium. The atria are added progressively from the caudal primary heart fields bilaterally, while the myocardium of the conotruncus is elongated from a midline secondary heart field of splanchnic mesoderm beneath the floor of the foregut. Cells in the secondary heart field express Nkx2.5 and Gata-4, as do the cells of the primary heart fields. Induction of myocardium appears to be unnecessary at the inflow pole, while it occurs at the outflow pole of the heart. Accretion of myocardium at the junction of the inflow myocardium with dorsal mesocardium is completed at stage 12 and later (stage 18) from the secondary heart field just caudal to the outflow tract. Induction of myocardium appears to move in a caudal direction as the outflow tract translocates caudally relative to the pharyngeal arches. As the cells in the secondary heart field begin to move into the outflow or inflow myocardium,they express HNK-1 initially and then MF-20, a marker for myosin heavy chain. FGF-8 and BMP-2 are present in the ventral pharynx and secondary heart field/outflow myocardium, respectively, and appear to effect induction of the cells in a manner that mimics induction of the primary myocardium from the primary heart fields. Neither FGF-8 nor BMP-2 is present as inflow myocardium is added from the primary heart fields. The addition of a secondary myocardium to the primary heart tube provides a new framework for understanding several null mutations in mice that cause defective heart development.

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Continuous addition of progenitors forms the cardiac ventricle in zebrafish

10.1101/230649 ◽

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.

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Molecular Embryogenesis of the Heart

Pediatric and Developmental Pathology ◽

10.1007/s10024-002-0004-2 ◽

2002 ◽

Vol 5 (6) ◽

pp. 516-543 ◽

Cited By ~ 54

Author(s):

Margaret L. Kirby ◽

Karen L. Waldo

Keyword(s):

Molecular Genetic ◽

Heart Tube ◽

Molecular Control ◽

Complex Process ◽

Molecular Genetic Basis ◽

Heart Field ◽

Endocardial Cell ◽

Heart Fields ◽

Secondary Heart Field ◽

Myocardial Differentiation

Development of the heart is a complex process involving primary and secondary heart fields that are set aside to generate myocardial and endocardial cell lineages. The molecular inductions that occur in the primary heart field appear to be recapitulated in induction and myocardial differentiation of the secondary heart field, which adds the conotruncal segments to the primary heart tube. While much is now known about the initial steps and factors involved in induction of myocardial differentiation, little is known about induction of endocardial development. Many of the genes expressed by nascent myocardial cells, which then become committed to a specific heart segment, have been identified and studied. In addition to the heart fields, several other “extracardiac” cell populations contribute to the fully functional mature heart. Less is known about the genetic programs of extracardiac cells as they enter the heart and take part in cardiogenesis. The molecular/genetic basis of many congenital cardiac defects has been elucidated in recent years as a result of new insights into the molecular control of developmental events.

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Outflow Tract Formation—Embryonic Origins of Conotruncal Congenital Heart Disease

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd8040042 ◽

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.

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Lamb1a regulates atrial growth by limiting excessive, contractility-dependent second heart field addition during zebrafish heart development

10.1101/2021.03.10.434727 ◽

2021 ◽

Author(s):

Christopher J. Derrick ◽

Eric J. G. Pollitt ◽

Ashley Sanchez Sevilla Uruchurtu ◽

Farah Hussein ◽

Emily S. Noёl

Keyword(s):

Heart Development ◽

Cardiac Development ◽

Basement Membranes ◽

Atrioventricular Canal ◽

Cardiac Morphogenesis ◽

Heart Morphogenesis ◽

Second Heart Field ◽

Heart Field ◽

Heart Size ◽

Zebrafish Heart

AbstractDuring early vertebrate heart development, the heart transitions from a linear tube to a complex asymmetric structure. This process includes looping of the tube and ballooning of the emerging cardiac chambers, which occur simultaneously with growth of the heart. A key driver of cardiac growth is deployment of cells from the Second Heart Field (SHF) into both poles of the heart, with cardiac morphogenesis and growth intimately linked in heart development. Laminin is a core component of extracellular matrix (ECM) basement membranes, and although mutations in specific laminin subunits are linked with a variety of cardiac abnormalities, including congenital heart disease and dilated cardiomyopathy, no role for laminin has been identified in early vertebrate heart morphogenesis. We identified dynamic, tissue-specific expression of laminin subunit genes in the developing zebrafish heart, supporting a role for laminins in heart morphogenesis.lamb1amutants exhibit cardiomegaly from 2dpf onwards, with subsequent progressive defects in cardiac morphogenesis characterised by a failure of the chambers to compact around the developing atrioventricular canal. We show that loss oflamb1aresults in excess addition of SHF cells to the atrium, revealing that Lamb1a functions to limit heart size during cardiac development by restricting SHF addition to the venous pole.lamb1amutants exhibit hallmarks of altered haemodynamics, and specifically blocking cardiac contractility inlamb1amutants rescues heart size and atrial SHF addition. Furthermore, we identify that FGF and RA signalling, two conserved pathways promoting SHF addition, are regulated by heart contractility and are dysregulated inlamb1amutants, suggesting that laminin mediates interactions between SHF deployment, heart biomechanics, and biochemical signalling during heart development. Together, this describes the first requirement for laminins in early vertebrate heart morphogenesis, reinforcing the importance of specialised ECM composition in cardiac development.

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Myocardial volume and organization are changed by failure of addition of secondary heart field myocardium to the cardiac outflow tract

Developmental Dynamics ◽

10.1002/dvdy.10364 ◽

2003 ◽

Vol 228 (2) ◽

pp. 152-160 ◽

Cited By ~ 32

Author(s):

T. Mesud Yelbuz ◽

Karen L. Waldo ◽

Xiaowei Zhang ◽

Marzena Zdanowicz ◽

Jeremy Parker ◽

...

Keyword(s):

Outflow Tract ◽

Heart Field ◽

Secondary Heart Field ◽

Cardiac Outflow

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Msx1 and Msx2 regulate survival of secondary heart field precursors and post-migratory proliferation of cardiac neural crest in the outflow tract

Developmental Biology ◽

10.1016/j.ydbio.2007.05.037 ◽

2007 ◽

Vol 308 (2) ◽

pp. 421-437 ◽

Cited By ~ 55

Author(s):

Yi-Hui Chen ◽

Mamoru Ishii ◽

Jingjing Sun ◽

Henry M. Sucov ◽

Robert E. Maxson

Keyword(s):

Neural Crest ◽

Outflow Tract ◽

Cardiac Neural Crest ◽

Heart Field ◽

Secondary Heart Field

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Hey2 restricts cardiac progenitor addition to the developing heart

10.1101/199638 ◽

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.

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

10.1101/2020.07.12.198994 ◽

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.

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

PLoS Biology ◽

10.1371/journal.pbio.3001200 ◽

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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Not Just Inductive: A Critical Mechanical Role for the Endoderm During Heart Tube Assembly

ASME 2012 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2012-80621 ◽

2012 ◽

Author(s):

Victor D. Varner ◽

Larry A. Taber

Keyword(s):

Close Contact ◽

Ventral Side ◽

Lateral Plate Mesoderm ◽

Heart Tube ◽

Lateral Plate ◽

Cardiac Progenitors ◽

Cardiac Specification ◽

Tube Assembly ◽

Heart Fields

The heart is the first functioning organ to form during development. Similar to other organ primordia, the embryonic heart forms as a simple tube — in this case, a straight muscle-wrapped tube situated on the ventral side of the embryo. During gastrulation, the cardiac progenitors reside in the lateral plate mesoderm but maintain close contact with the underlying endoderm. In amniotes, these bilateral heart fields are initially organized as a pair of flat epithelia that move toward the embryonic midline and fuse above the anterior intestinal portal (AIP) to form the heart tube. This medial motion is typically attributed to active mesodermal migration over the underlying endoderm. In this view, the role of the endoderm is two-fold: to serve as a mechanically passive substrate for the crawling mesoderm and to secrete various growth factors necessary for cardiac specification and differentiation.

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