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.

scholarly journals Homeobox Transcription Factor Prox1 in Sympathetic Ganglia of Vertebrate Embryos: Correlation With Human Stage 4s Neuroblastoma

2010 ◽  
Vol 68 (2) ◽  
pp. 112-117 ◽  
Author(s):  
Jürgen Becker ◽  
Baigang Wang ◽  
Helena Pavlakovic ◽  
Kerstin Buttler ◽  
Jörg Wilting
Keyword(s):  
Transcription Factor ◽  
Sympathetic Ganglia ◽  
Homeobox Transcription Factor ◽  
Vertebrate Embryos

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 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 Inhibition of transcription factor GATA-4 expression blocks in vitro cardiac muscle differentiation.

1995 ◽  
Vol 15 (8) ◽  
pp. 4095-4102 ◽  
Author(s):  
C Grépin ◽  
L Robitaille ◽  
T Antakly ◽  
M Nemer
Keyword(s):  
Transcription Factor ◽  
Cardiac Muscle ◽  
Heart Development ◽  
Muscle Cells ◽  
Cardiac Differentiation ◽  
Marker Genes ◽  
Early Event ◽  
Heart Tube ◽  
Cardiac Muscle Cells ◽  
Cardiac Lineage

Commitment of mesodermal cells to the cardiac lineage is a very early event that occurs during gastrulation, and differentiation of cardiac muscle cells begins in the presomite stage prior to formation of the beating heart tube. However, the molecular events, including gene products that are required for differentiation of cardiac muscle cells, remain essentially unknown. GATA-4 is a recently characterized cardiac muscle-restricted transcription factor whose properties suggest an important regulatory role in heart development. We tested the role of GATA-4 in cardiac differentiation, using the pluripotent P19 embryonal carcinoma cells, which can be differentiated into beating cardiac muscle cells. In this system, GATA-4 transcripts and protein are restricted to cells committed to the cardiac lineage, and induction of GATA-4 precedes expression of cardiac marker genes and appearance of beating cells. Inhibition of GATA-4 expression by antisense transcripts blocks development of beating cardiac muscle cells and interferes with expression of cardiac muscle markers. These data indicate that GATA-4 is necessary for development of cardiac muscle cells and identify for the first time a tissue-specific transcription factor that may be crucial for early steps of mammalian cardiogenesis.

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.

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 Regulation of EphA8 Gene Expression by TALE Homeobox Transcription Factors during Development of the Mesencephalon

2006 ◽  
Vol 27 (5) ◽  
pp. 1614-1630 ◽  
Author(s):  
Sungbo Shim ◽  
Yujin Kim ◽  
Jongdae Shin ◽  
Jieun Kim ◽  
Soochul Park
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Transcriptional Activation ◽  
Regulatory Region ◽  
Dominant Negative ◽  
Regulatory Sequence ◽  
Enhancer Activity ◽  
Homeobox Transcription Factor ◽  
Homeobox Transcription Factors

ABSTRACT The mouse ephA8 gene is expressed in a rostral-to-caudal gradient in the developing superior colliculus, and these EphA gradients may contribute to the proper development of the retinocollicular projection. Thus, it is of considerable interest to elucidate how the ephA8 gene expression is controlled by upstream regulators during the development of the mesencephalon. In this study, we employed in vivo expression analysis in transgenic mouse embryos to dissect the cis-acting DNA regulatory region, leading to the identification of a CGGTCA sequence critical for the ephA8 enhancer activity. Using this element as the target in a yeast one-hybrid system, we identified a Meis homeobox transcription factor. Significantly, DNA binding sites for Pbx, another TALE homeobox transcription factor, were also identified in the ephA8 enhancer region. Meis2 and Pbx1/2 are specifically expressed in the entire region of the dorsal mesencephalon, where specific colocalization of EphA8 and Meis is restricted to a subset of cells. Meis2 and Pbx2 synergistically bind the ephA8 regulatory sequence in vitro, and this interaction is critical for the transcriptional activation of a reporter construct bearing the ephA8 regulatory region in the presence of histone deacetylase inhibitor. More importantly, when expressed in the embryonic midbrain, the dominant-negative form of Meis down-regulates endogenous ephA8. Interestingly, we found that both Meis2 and Pbx2 are constitutively bound in the ephA8 regulatory region in the dorsal mesencephalon. These studies strongly suggest that Meis and Pbx homeobox transcription factors tightly associate with the ephA8 regulatory sequence and require an additional unidentified regulator to ensure the specific activation of ephA8.

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 Requirement of the LIM Homeodomain Transcription Factor Tailup for Normal Heart and Hematopoietic Organ Formation in Drosophila melanogaster

2007 ◽  
Vol 27 (11) ◽  
pp. 3962-3969 ◽  
Author(s):  
Ye Tao ◽  
Jianbo Wang ◽  
Tsuyoshi Tokusumi ◽  
Kathleen Gajewski ◽  
Robert A. Schulz
Keyword(s):  
Transcription Factor ◽  
Drosophila Melanogaster ◽  
Heart Development ◽  
Lymph Gland ◽  
Dorsal Vessel ◽  
Heart Tube ◽  
Hematopoietic Organ ◽  
Homeodomain Transcription Factor ◽  
Pericardial Cells ◽  
Lim Homeodomain

ABSTRACT Dorsal vessel morphogenesis in Drosophila melanogaster serves as a superb system with which to study the cellular and genetic bases of heart tube formation. We used a cardioblast-expressed Toll-GFP transgene to screen for additional genes involved in heart development and identified tailup as a locus essential for normal dorsal vessel formation. tailup, related to vertebrate islet1, encodes a LIM homeodomain transcription factor expressed in all cardioblasts and pericardial cells of the heart tube as well as in associated lymph gland hematopoietic organs and alary muscles that attach the dorsal vessel to the epidermis. A transcriptional enhancer regulating expression in these four cell types was identified and used as a tailup-GFP transgene with additional markers to characterize dorsal vessel defects resulting from gene mutations. Two reproducible phenotypes were observed in mutant embryos: hypoplastic heart tubes with misaligned cardioblasts and the absence of most lymph gland and pericardial cells. Conversely, a significant expansion of the lymph glands and abnormal morphology of the heart were observed when tailup was overexpressed in the mesoderm. Tailup was shown to bind to two DNA recognition sequences in the dorsal vessel enhancer of the Hand basic helix-loop-helix transcription factor gene, with one site proven to be essential for the lymph gland, pericardial cell, and Svp/Doc cardioblast expression of Hand. Together, these results establish Tailup as being a critical new transcription factor in dorsal vessel morphogenesis and lymph gland formation and place this regulator directly upstream of Hand in these developmental processes.

The homeobox transcription factor HoxC9, a key regulator of development, suppresses tumourigenicity of neuroblastoma

2010 ◽  
Vol 222 (03) ◽  
Author(s):  
H Kocak ◽  
S Ackermann ◽  
B Hero ◽  
Y Kahlert ◽  
J Theissen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Homeobox Transcription Factor
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