scholarly journals Myc overexpression enhances epicardial contribution to the developing heart and promotes extensive expansion of the cardiomyocyte population

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Cristina Villa del Campo ◽  
Ghislaine Lioux ◽  
Rita Carmona ◽  
Rocío Sierra ◽  
Ramón Muñoz-Chápuli ◽  
...  
Keyword(s):  
Cardiac Development ◽  
Initial Distribution ◽  
Initial Population ◽  
Cell Competition ◽  
Epicardial Cells ◽  
Developing Heart ◽  
Heart Repair ◽  
Homeostatic Expansion ◽  
Differential Expansion ◽  
Cell Growth And Proliferation

Abstract Myc is an essential regulator of cell growth and proliferation. Myc overexpression promotes the homeostatic expansion of cardiomyocyte populations by cell competition, however whether this applies to other cardiac lineages remains unknown. The epicardium contributes signals and cells to the developing and adult injured heart and exploring strategies for modulating its activity is of great interest. Using inducible genetic mosaics, we overexpressed Myc in the epicardium and determined the differential expansion of Myc-overexpressing cells with respect to their wild type counterparts. Myc-overexpressing cells overcolonized all epicardial-derived lineages and showed increased ability to invade the myocardium and populate the vasculature. We also found massive colonization of the myocardium by Wt1Cre-derived Myc-overexpressing cells, with preservation of cardiac development. Detailed analyses showed that this contribution is unlikely to derive from Cre activity in early cardiomyocytes but does not either derive from established epicardial cells, suggesting that early precursors expressing Wt1Cre originate the recombined cardiomyocytes. Myc overexpression does not modify the initial distribution of Wt1Cre-recombined cardiomyocytes, indicating that it does not stimulate the incorporation of early expressing Wt1Cre lineages to the myocardium, but differentially expands this initial population. We propose that strategies using epicardial lineages for heart repair may benefit from promoting cell competitive ability.

scholarly journals Mammalian E4 Is Required for Cardiac Development and Maintenance of the Nervous System

2005 ◽  
Vol 25 (24) ◽  
pp. 10953-10964 ◽  
Author(s):  
Chie Kaneko-Oshikawa ◽  
Tadashi Nakagawa ◽  
Mitsunori Yamada ◽  
Hiroo Yoshikawa ◽  
Masaki Matsumoto ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Cardiac Muscle ◽  
Cardiac Development ◽  
Physiological Function ◽  
Embryonic Fibroblasts ◽  
Adult Mice ◽  
Developing Heart ◽  
Ubiquitin Conjugation ◽  
Spinocerebellar Neurons

ABSTRACT Ubiquitin conjugation typically requires three classes of enzyme: E1, E2, and E3. A fourth type of enzyme (E4), however, was recently shown to be required for the degradation of certain types of substrate in yeast. We previously identified UFD2a (also known as E4B) as an E4 in mammals. UFD2a is exclusively expressed in cardiac muscle during mouse embryonic development, but it is abundant in neurons of adult mice and is implicated in the pathogenesis of neurodegenerative disease. The precise physiological function of this enzyme has remained largely unknown, however. Here, we show that mice lacking UFD2a die in utero, manifesting marked apoptosis in the developing heart. Polyubiquitylation activity for an E4 substrate was greatly reduced in Ufd2a −/− mouse embryonic fibroblasts. Furthermore, Ufd2a +/− mice displayed axonal dystrophy in the nucleus gracilis, as well as degeneration of Purkinje cells accompanied by endoplasmic reticulum stress. These animals also developed a neurological disorder. UFD2a thus appears to be essential for the development of cardiac muscle, as well as for the protection of spinocerebellar neurons from degeneration induced by endoplasmic reticulum stress.

scholarly journals CHD4 and the NuRD complex directly control cardiac sarcomere formation

2018 ◽  
Vol 115 (26) ◽  
pp. 6727-6732 ◽  
Author(s):  
Caralynn M. Wilczewski ◽  
Austin J. Hepperla ◽  
Takashi Shimbo ◽  
Lauren Wasson ◽  
Zachary L. Robbe ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Transcriptional Control ◽  
Cardiac Development ◽  
Nurd Complex ◽  
Catalytic Core ◽  
Nucleosome Remodeling ◽  
Cardiac Sarcomere ◽  
Developing Heart ◽  
Genome Wide ◽  
Formation Function

Cardiac development relies on proper cardiomyocyte differentiation, including expression and assembly of cell-type-specific actomyosin subunits into a functional cardiac sarcomere. Control of this process involves not only promoting expression of cardiac sarcomere subunits but also repressing expression of noncardiac myofibril paralogs. This level of transcriptional control requires broadly expressed multiprotein machines that modify and remodel the chromatin landscape to restrict transcription machinery access. Prominent among these is the nucleosome remodeling and deacetylase (NuRD) complex, which includes the catalytic core subunit CHD4. Here, we demonstrate that direct CHD4-mediated repression of skeletal and smooth muscle myofibril isoforms is required for normal cardiac sarcomere formation, function, and embryonic survival early in gestation. Through transcriptomic and genome-wide analyses of CHD4 localization, we identified unique CHD4 binding sites in smooth muscle myosin heavy chain, fast skeletal α-actin, and the fast skeletal troponin complex genes. We further demonstrate that in the absence of CHD4, cardiomyocytes in the developing heart form a hybrid muscle cell that contains cardiac, skeletal, and smooth muscle myofibril components. These misexpressed paralogs intercalate into the nascent cardiac sarcomere to disrupt sarcomere formation and cause impaired cardiac function in utero. These results demonstrate the genomic and physiological requirements for CHD4 in mammalian cardiac development.

The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development

Development ◽  
1999 ◽  
Vol 126 (6) ◽  
pp. 1269-1280 ◽  
Author(s):  
M. Tanaka ◽  
Z. Chen ◽  
S. Bartunkova ◽  
N. Yamasaki ◽  
S. Izumo
Keyword(s):  
Cardiac Myocytes ◽  
Heart Development ◽  
Cardiac Development ◽  
Es Cells ◽  
Homeobox Gene ◽  
Yolk Sac ◽  
Tunel Staining ◽  
Mesoderm Specification ◽  
Developing Heart ◽  
Heart Looping

Csx/Nkx2.5 is a vertebrate homeobox gene with a sequence homology to the Drosophila tinman, which is required for the dorsal mesoderm specification. Recently, heterozygous mutations of this gene were found to cause human congenital heart disease (Schott, J.-J., Benson, D. W., Basson, C. T., Pease, W., Silberbach, G. M., Moak, J. P., Maron, B. J., Seidman, C. E. and Seidman, J. G. (1998) Science 281, 108–111). To investigate the functions of Csx/Nkx2.5 in cardiac and extracardiac development in the vertebrate, we have generated and analyzed mutant mice completely null for Csx/Nkx2.5. Homozygous null embryos showed arrest of cardiac development after looping and poor development of blood vessels. Moreover, there were severe defects in vascular formation and hematopoiesis in the mutant yolk sac. Interestingly, TUNEL staining and PCNA staining showed neither enhanced apoptosis nor reduced cell proliferation in the mutant myocardium. In situ hybridization studies demonstrated that, among 20 candidate genes examined, expression of ANF, BNP, MLC2V, N-myc, MEF2C, HAND1 and Msx2 was disturbed in the mutant heart. Moreover, in the heart of adult chimeric mice generated from Csx/Nkx2.5 null ES cells, there were almost no ES cell-derived cardiac myocytes, while there were substantial contributions of Csx /Nkx2.5-deficient cells in other organs. Whole-mount β-gal staining of chimeric embryos showed that more than 20% contribution of Csx/Nkx2. 5-deficient cells in the heart arrested cardiac development. These results indicate that (1) the complete null mutation of Csx/Nkx2.5 did not abolish initial heart looping, (2) there was no enhanced apoptosis or defective cell cycle entry in Csx/Nkx2.5 null cardiac myocytes, (3) Csx/Nkx2.5 regulates expression of several essential transcription factors in the developing heart, (4) Csx/Nkx2.5 is required for later differentiation of cardiac myocytes, (5) Csx/Nkx2. 5 null cells exert dominant interfering effects on cardiac development, and (6) there were severe defects in yolk sac angiogenesis and hematopoiesis in the Csx/Nkx2.5 null embryos.

Halton Based Initial Distribution in Artificial Bee Colony Algorithm and its Application in Software Effort Estimation

2012 ◽  
Vol 3 (2) ◽  
pp. 86-106 ◽  
Author(s):  
Tarun Kumar Sharma ◽  
Millie Pant
Keyword(s):  
Optimization Algorithm ◽  
Artificial Bee Colony ◽  
Real Life ◽  
Initial Distribution ◽  
Benchmark Problems ◽  
Model Parameters ◽  
Random Numbers ◽  
Initial Population ◽  
Effort Estimation ◽  
Bee Colony

Artificial Bee Colony (ABC) is an optimization algorithm that simulates the foraging behavior of honey bees. It is a population based search technique whose performance depends largely on the distribution of initial population. Generally, uniform distributions are preferred since they best reflect the lack of knowledge about the optimum’s location. Moreover, these are easy to generate as most of the programming languages have an inbuilt function for generating uniformly distributed random numbers. However, in case of a population dependent optimization algorithm like that of ABC, random numbers having uniform probability distribution may not be a good choice as they may not be able exploit the search space fully. This paper uses quasi random numbers based on Halton sequence for the initial distribution and have compared the simulation results with initial population generated using uniform distribution. The proposed variant, termed as Halton based ABC (H-ABC), is validated on a set of 15 standard benchmark problems, 6 nontraditional shifted benchmark functions proposed at the special session of CEC2008, and has been used for solving the real life problem of estimating the cost model parameters. Numerical results indicate the competence of the proposed algorithm.

Expression of Discoidin Domain Receptor 2 (DDR2) in the Developing Heart

2005 ◽  
Vol 11 (3) ◽  
pp. 260-267 ◽  
Author(s):  
Mary O. Morales ◽  
Robert L. Price ◽  
Edie C. Goldsmith
Keyword(s):  
Extracellular Matrix ◽  
Cardiac Development ◽  
Cardiac Fibroblasts ◽  
Matrix Proteins ◽  
Collagen Types ◽  
Discoidin Domain Receptor ◽  
Developing Heart ◽  
Discoidin Domain Receptor 2 ◽  
Endocardial Surface ◽  
Coronary Endothelium

Interactions between cells and the surrounding extracellular matrix are important for a number of developmental events. In the heart, cardiac fibroblasts produce the majority of extracellular matrix proteins, particularly collagen types I and III. Cells originating from the proepicardial organ migrate over the surface of the heart, invade the underlying myocardium and ultimately give rise to smooth muscle cells, fibroblasts, and coronary endothelium. Although integrin expression in the developing heart has been well characterized, the expression of Discoidin Domain Receptor 2 (DDR2) remains to be defined. Using confocal microscopy, the expression of DDR2 was examined at several points during cardiac development. Initially, DDR2 expression was detected on the epicardial surface of the heart and on endothelial and mesenchymal cells within the cardiac cushions. As development progressed, DDR2 expression increased at localized regions in the apex and atrioventricular sulcus, although this expression decreased from epicardial to endocardial surface. Eventually, DDR2 expression spanned the myocardial free wall and was detected within the septum. Not until postnatal development was DDR2 expression detected uniformly throughout the myocardium and this distribution was maintained in the adult heart. In summary, the data presented demonstrate that the distribution of DDR2-positive cells changes within the heart during development.

scholarly journals Arylamine N-acetyltransferase 2 Expression in the Developing Heart

2005 ◽  
Vol 53 (5) ◽  
pp. 583-592 ◽  
Author(s):  
Larissa Wakefield ◽  
Valerie Cornish ◽  
Fiona Broackes-Carter ◽  
Edith Sim
Keyword(s):  
Cardiac Tissue ◽  
Cardiac Development ◽  
Sinus Node ◽  
Circulation Pattern ◽  
Right Atrial ◽  
Developing Heart ◽  
Right Atrial Appendage ◽  
The Right

Murine arylamine N-acetyltransferase 2 (NAT2) is expressed in the developing heart and in the neural tube at the time of closure. Classically described as a xenobiotic metabolizing enzyme, there is increasing evidence for a distinct biological role for murine NAT2. We have characterized the expression of arylamine N-acetyltransferase 2 during cardiogenesis, mapping its expression in vivo, using a lacZ insertion deletion, and also in vitro, by measuring NAT2 enzyme activity. These findings show that cardiac Nat2 expression is both temporally and spatially regulated during development. In neonatal mice, cardiac Nat2 expression is most extensive in the central fibrous body and is evident in the atrioventricular valves and the valves of the great vessels. Whereas Nat2 expression is not detected in ventricular myocardial cells, Nat2 is strongly expressed in scattered cells in the region of the sinus node, the epicardium of the right atrial appendage, and in the pulmonary artery. Expression of active NAT2 protein is maximal when the developing heart attains the adult circulation pattern and moves from metabolizing glucose to fatty acids. NAT2 acetylating activity in cardiac tissue from Nat2−/- and Nat2+/- mice indicates a lack of compensating acetylating activity either from other acetylating enzymes or by NAT2 encoded by the wild-type Nat2 allele in Nat2+/- heterozygotes. The temporal and spatial control of murine Nat2 expression points to an endogenous role distinct from xenobiotic metabolism and indicates that Nat2 expression may be useful as a marker in cardiac development.

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.

scholarly journals The “memory” of the Oort cloud

2018 ◽  
Vol 620 ◽  
pp. A45 ◽  
Author(s):  
Marc Fouchard ◽  
Arika Higuchi ◽  
Takashi Ito ◽  
Lucie Maquet
Keyword(s):  
Initial Distribution ◽  
Oort Cloud ◽  
Cloud Formation ◽  
Orbital Energy ◽  
Initial Population ◽  
Isotropic Model ◽  
Initial Shape ◽  
Long Period ◽  
Galactic Longitude

Aims. Our aim in this paper is to try to discover if we can find any record of the Oort cloud formation process in the orbital distribution of currently observable long-periodic comets. Methods. Long-term simulations of tens of millions of comets from two different kinds of proto-Oort clouds (isotropic and disk-like) were performed. In these simulations we considered the Galactic tides, stellar passage, and planetary perturbations. Results. In the case of an initially disk-like proto-Oort cloud, the final Oort cloud remains anisotroic inside of about 13 200 au. A record of the initial shape is preserved, here referred to as the “memory”, even on the final distribution of observable comets. This memory is measurable in particular for observable comets for which the previous perihelion was beyond 10 au and that were significantly affected by Uranus or Neptune at that moment (the so-called Kaib-Quinn jumpers observable class). Indeed, these comets are strongly concentrated along an extended scattered disk that is the remnant of the initial population 1 Gyr before the comets are observable. In addition, for this class of comets, the distributions of ecliptic inclination and Galactic longitude of the ascending node at the previous perihelion preceding the observable perihelion highlight characteristics that are not present in the isotropic model. Furthermore, the disk-like model produces four times more observable comets than the isotropic one, and its flux is independent of the initial distribution of orbital energy. Also for the disk-like model, the region beyond Neptune up to ~40 au gives the major contribution to the final flux of observable comets. Conclusions. The disk-like model sustains a flux of observable comets that are more consistent with the actually observed flux than using the isotropic model. However, further investigations are needed to reveal whether a fingerprint of the initial proto-Oort cloud, such as those highlighted in the present article, is present in the sample of known long-period comets.

scholarly journals Origin of congenital coronary arterio-ventricular fistulae from anomalous epicardial and myocardial development

2022 ◽  
Author(s):  
Paul Palmquist-Gomes ◽  
Adrian Ruiz-Villalba ◽  
Juan Antonio Guadix ◽  
Juan Pablo Romero ◽  
Bettina Bessieres ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Coronary Artery ◽  
Congenital Anomalies ◽  
Molecular Mechanisms ◽  
Relevant Information ◽  
Ventricular Wall ◽  
Coronary Smooth Muscle ◽  
Epicardial Cells ◽  
Developing Heart

Coronary Artery Fistulae (CAFs) are cardiac congenital anomalies consisting of an abnormal communication of a coronary artery with either a cardiac chamber or another cardiac vessel. In humans, these congenital anomalies can lead to complications such as myocardial hypertrophy, endocarditis, heart dilatation and failure. Unfortunately, despite their clinical relevance, the aetiology of CAFs remains unknown. In this work, we have used two different species (mouse and avian embryos) to experimentally model CAFs morphogenesis. Both conditional Itga4 (alpha 4 integrin) epicardial deletion in mice and cryocauterisation of chick embryonic hearts disrupted epicardial development and ventricular wall growth, two essential events in coronary embryogenesis. Additional transcriptomics and in vitro analyses were performed to better understand how arterio-ventricular connections are originated in the embryonic heart. Our results suggest myocardial discontinuities in the developing heart promote the formation of endocardial pouch-like structures resembling human CAF. The structure of these CAF-like anomalies was compared with histopathological data from a paediatric heart CAF, showing histomorphological and immunochemical similarities, including an accumulation of smooth muscle positive cells in the pouch-like structure wall. In vitro experiments showed the abnormal contact between the epicardium and the endocardium may promote the precocious differentiation of epicardial cells to smooth muscle. Our results suggest that myocardial discontinuities in the embryonic ventricular wall promote the early contact of the endocardium with epicardial-derived coronary progenitors at the cardiac surface, leading to ventricular endocardial extrusion, precocious differentiation of coronary smooth muscle cells, and the formation of pouch-like aberrant coronary-like structures in direct connection with the ventricular lumen. Our results may provide relevant information for the early diagnosis of these congenital anomalies and the molecular mechanisms that regulate their embryogenesis.

scholarly journals Downregulation of WT1 transcription factor gene expression is required to promote myocardial fate

2021 ◽  
Author(s):  
Ines J Marques ◽  
Alexander Ernst ◽  
Prateek Arora ◽  
Andrej Vianin ◽  
Tanja Hetke ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cardiac Development ◽  
Wilms Tumor ◽  
Ectopic Expression ◽  
Heart Tube ◽  
Adhesion Properties ◽  
Epicardial Cells ◽  
Sarcomere Assembly ◽  
Myocardial Differentiation

During cardiac development, cells from the precardiac mesoderm fuse to form the primordial heart tube, which then grows by addition of further progenitors to the venous and arterial poles. In the zebrafish, wilms tumor 1 transcription factor a (wt1a) and b (wt1b) are expressed in the pericardial mesoderm at the venous pole of the forming heart tube. The pericardial mesoderm forms a single layered mesothelial sheet that contributes to further the growth of the myocardium, and forms the proepicardium. Proepicardial cells are subsequently transferred to the myocardial surface and give rise to the epicardium, the outer layer covering the myocardium in the adult heart. wt1a/b expression is downregulated during the transition from pericardium to myocardium, but remains high in proepicardial cells. Here we show that sustained wt1 expression impaired cardiomyocyte maturation including sarcomere assembly, ultimately affecting heart morphology and cardiac function. ATAC-seq data analysis of cardiomyocytes overexpressing wt1 revealed that chromatin regions associated with myocardial differentiation genes remain closed upon wt1b overexpression in cardiomyocytes, suggesting that wt1 represses a myocardial differentiation program. Indeed, a subset of wt1a/b-expressing cardiomyocytes changed their cell adhesion properties, delaminated from the myocardial epithelium, and upregulated the expression of epicardial genes, as confirmed by in vivo imaging. Thus, we conclude that wt1 acts as a break for cardiomyocyte differentiation by repressing chromatin opening at specific genomic loci and that sustained ectopic expression of wt1 in cardiomyocytes can lead to their transformation into epicardial cells.

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