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 Conotruncal myocardium arises from a secondary heart field

Development ◽  
2001 ◽  
Vol 128 (16) ◽  
pp. 3179-3188 ◽  
Author(s):  
Karen L. Waldo ◽  
Donna H. Kumiski ◽  
Kathleen T. Wallis ◽  
Harriett A. Stadt ◽  
Mary. R. Hutson ◽  
...  
Keyword(s):  
Heart Development ◽  
Outflow Tract ◽  
Heart Tube ◽  
In Ovo ◽  
Atrioventricular Canal ◽  
Lateral Plate ◽  
Heart Field ◽  
Dorsal Mesocardium ◽  
Heart Fields ◽  
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.

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 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.

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.

Tbx5 is essential for heart development

Development ◽  
1999 ◽  
Vol 126 (8) ◽  
pp. 1739-1751 ◽  
Author(s):  
M.E. Horb ◽  
G.H. Thomsen
Keyword(s):  
Transcription Factor ◽  
Heart Development ◽  
Dominant Negative ◽  
Heart Tube ◽  
Anterior Portion ◽  
Septal Defects ◽  
Cardiac Specification ◽  
Homeobox Transcription Factor ◽  
Heart Field ◽  
Vertebrate Embryos

Mutations in the Tbx5 transcription factor cause heart septal defects found in human Holt-Oram Syndrome. The complete extent to which Tbx5 functions in heart development, however, has not been established. Here we show that, in Xenopus embryos, Tbx5 is expressed in the early heart field, posterior to the cardiac homeobox transcription factor, Nkx2.5. During morphogenesis, Tbx5 is expressed throughout the heart tube except the anterior portion, the bulbus cordis. When Tbx5 activity is antagonized with a hormone-inducible, dominant negative version of the protein, the heart fails to develop. These results suggest that, in addition to its function in heart septation, Tbx5 has a more global role in cardiac specification and heart development in vertebrate embryos.

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.

scholarly journals Tbx5 drives aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Scott A Rankin ◽  
Jeffrey D Steimle ◽  
Xinan H Yang ◽  
Ariel B Rydeen ◽  
Kunal Agarwal ◽  
...  
Keyword(s):  
Heart Development ◽  
Hedgehog Signaling ◽  
Regulatory Networks ◽  
Lateral Plate ◽  
T Box ◽  
Regulatory Module ◽  
Terrestrial Life ◽  
Heart Field ◽  
Gene Regulatory ◽  
Foregut Endoderm

The gene regulatory networks that coordinate the development of the cardiac and pulmonary systems are essential for terrestrial life but poorly understood. The T-box transcription factor Tbx5 is critical for both pulmonary specification and heart development, but how these activities are mechanistically integrated remains unclear. Here using Xenopus and mouse embryos, we establish molecular links between Tbx5 and retinoic acid (RA)-signaling in the mesoderm and between RA signaling and sonic hedgehog expression in the endoderm to unveil a conserved RA-Hedgehog-Wnt signaling cascade coordinating cardiopulmonary development. We demonstrate that Tbx5 directly maintains expression of aldh1a2, the RA-synthesizing enzyme, in the foregut lateral plate mesoderm via an evolutionarily conserved intronic enhancer. Tbx5 promotes posterior second heart field identity in a positive feedback loop with RA, antagonizing a Fgf8-Cyp regulatory module to restrict FGF activity to the anterior. We find that Tbx5/Aldh1a2-dependent RA signaling directly activates shh transcription in the adjacent foregut endoderm through a conserved MACS1 enhancer. Hedgehog signaling coordinates with Tbx5 in the mesoderm to activate expression of wnt2/2b, which induces pulmonary fate in the foregut endoderm. These results provide mechanistic insight into the interrelationship between heart and lung development informing cardiopulmonary evolution and birth defects.

scholarly journals Understanding Mechanisms of Chamber-Specific Differentiation Through Combination of Lineage Tracing and Single Cell Transcriptomics

2021 ◽  
Author(s):  
David M Gonzalez ◽  
Nadine Schrode ◽  
Tasneem Ebrahim ◽  
Kristin G Beaumont ◽  
Robert Sebra ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Single Cell ◽  
Cardiac Development ◽  
Cell Types ◽  
Myocardial Cell ◽  
Lineage Tracing ◽  
Metabolic Processes ◽  
Heart Tube ◽  
Heart Field ◽  
Bona Fide

The specification and differentiation of atrial and ventricular myocardial cell types during development is incompletely understood. We have previously shown that Foxa2 expression during gastrulation identifies a population of ventricular fated progenitors, allowing for labeling of these cells prior to the morphogenetic events that lead to chamber formation and acquisition of bona fide atrial or ventricular identity. In this study, we performed single cell RNA sequencing of Foxa2Cre;mTmG embryos at the cardiac crescent (E8.25), primitive heart tube (E8.75) and heart tube (E9.25) stage in order to understand the transcriptional mechanisms underlying formation of atrial and ventricular cell types at the earliest stages of cardiac development. We find that progression towards differentiated myocardial cell types occurs primarily based on heart field progenitor identity, and that different progenitor populations contribute to ventricular or atrial identity through separate differentiation mechanisms. We identified a number of candidate markers that define such differentiation processes, as well as differential regulation of metabolic processes that distinguish atrial and ventricular fated cells at the earliest stages of development. We further show that exogenous injection with retinoic acid during formation of the cardiac primordia causes defects in ventricular chamber size and is associated with dysregulation in FGF signaling in anterior second heart field cells and a shunt in differentiation towards orthogonal lineages. Retinoic acid also causes defects in cell-cycle exit in myocardial committed progenitors that result in formation of hypomorphic ventricles with decreased expression of important metabolic processes and sarcomere assembly. Collectively, our data identify, at a single cell level, distinct lineage trajectories during cardiac progenitor cell specification and differentiation, and the precise effects of manipulating cardiac progenitor field patterning via exogenous retinoic acid signaling.

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