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.

Kersti K. Linask

Michael VanAuker

A Role for the Cytoskeleton in Heart Looping

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.

Loretta L. Hoover

Elizabeth G. Burton

Bonnie A. Brooks

Steven W. Kubalak

The Expanding Role for Retinoid Signaling in Heart Development

The cardiac conduction system (CCS) encompasses a complex system responsible for the coordinated contraction of the heart. In the developing heart, as well as in the adult heart, tissues of the (putative) CCS are characterized by different properties than the surrounding working myocardium, which can be observed on a histological level, as well as by the expression patterns of several immunohistological and molecular markers. In recent years, many markers have been studied that have helped to elucidate the processes involved in CCS development. It has become clear that multiple genes, cells and their interactions are involved in this complex process. In this article, an overview of the current knowledge of CCS development is supplied. Furthermore, several controversies regarding conduction system development are discussed, as well as the possible significance of embryologic development of the CCS for the development of arrhythmias later in life.

M. R. M. Jongbloed

E. A. F. Mahtab

N. A. Blom

M. J. Schalij

A. C. Gittenberger-de Groot

Development of the Cardiac Conduction System and the Possible Relation to Predilection Sites of Arrhythmogenesis

Cardiovascular development is directed or modulated by genetic and epigenetic factors. The latter include blood flow-related shear stress and blood pressure-related circumferential strain. This review focuses on shear stress and its effects on endothelial cells lining the inner surfaces of the heart and blood vessels. Flow characteristics of the embryonic blood, like velocity, viscosity and periodicity, are taken into account to describe the responses of endothelial cells to shear stress and the sensors for this friction force. The primary cilium, which is an integral part of the shear sensor, connects to the cytoskeletal microtubules and transmits information about the level and direction of blood flow into the endothelial cell. When the heart remodels from a more or less straight into a c-shaped tube the sharp curvature, in combination with the small vessel dimensions and high relative viscosity, directs the highest shear stress to the inner curvature of this pump. This proves to be an important epigenetic modulator of cardiac morphogenesis because when shear stress is experimentally altered inner curvature remodeling is affected which leads to the development of congenital cardiovascular anomalies. The best of both worlds, mechanics and biology, are used here to describe early cardiogenesis.

Beerend P. Hierck

Kim Van der Heiden

Christian Poelma

Jerry Westerweel

Robert E. Poelmann

Fluid Shear Stress and Inner Curvature Remodeling of the Embryonic Heart. Choosing the Right Lane!

Adriana C. Gittenberger-de Groot

Cardiac Development

Wnts are a family of secreted signaling proteins that are encoded by 19 distinct genes in the vertebrate genome. These molecules initiate several signal transduction pathways: the canonical Wnt, Wnt/Ca2+, and Wnt/planar cell polarity pathways. Wnt proteins have major impact on embryonic development, tumor progression, and stem cell differentiation. Wnt signal transduction also influences the formation of the heart, yet many issues concerning the involvement of Wnt regulation in initiating cardiac development remain unresolved. In this review, we will examine the published record to discern (a) what has been shown by experimental studies on the participation of Wnt signaling in cardiogenesis, and (b) what are the important questions that need to be addressed to understand the importance and function of Wnt signal transduction in facilitating the development of the heart.

Leonard M. Eisenberg

Carol A. Eisenberg

Evaluating the Role of Wnt Signal Transduction in Promoting the Development of the Heart

Although it is well established that transgenic manipulation of mammalian neural crest-related gene expression and microsurgical removal of premigratory chicken and Xenopus embryonic cardiac neural crest progenitors results in a wide spectrum of both structural and functional congenital heart defects, the actual functional mechanism of the cardiac neural crest cells within the heart is poorly understood. Neural crest cell migration and appropriate colonization of the pharyngeal arches and outflow tract septum is thought to be highly dependent on genes that regulate cell-autonomous polarized movement (i.e., gap junctions, cadherins, and noncanonical Wnt1 pathway regulators). Once the migratory cardiac neural crest subpopulation finally reaches the heart, they have traditionally been thought to participate in septation of the common outflow tract into separate aortic and pulmonary arteries. However, several studies have suggested these colonizing neural crest cells may also play additional unexpected roles during cardiovascular development and may even contribute to a crest-derived stem cell population. Studies in both mice and chick suggest they can also enter the heart from the venous inflow as well as the usual arterial outflow region, and may contribute to the adult semilunar and atrioventricular valves as well as part of the cardiac conduction system. Furthermore, although they are not usually thought to give rise to the cardiomyocyte lineage, neural crest cells in the zebrafish (Danio rerio) can contribute to the myocardium and may have different functions in a species-dependent context. Intriguingly, both ablation of chick and Xenopus premigratory neural crest cells, and a transgenic deletion of mouse neural crest cell migration or disruption of the normal mammalian neural crest gene expression profiles, disrupts ventral myocardial function and/or cardiomyocyte proliferation. Combined, this suggests that either the cardiac neural crest secrete factor/s that regulate myocardial proliferation, can signal to the epicardium to subsequently secrete a growth factor/s, or may even contribute directly to the heart. Although there are species differences between mouse, chick, and Xenopus during cardiac neural crest cell morphogenesis, recent data suggest mouse and chick are more similar to each other than to the zebrafish neural crest cell lineage. Several groups have used the genetically defined Pax3 (splotch) mutant mice model to address the role of the cardiac neural crest lineage. Here we review the current literature, the neural crest-related role of the Pax3 transcription factor, and discuss potential function/s of cardiac neural crest-derived cells during cardiovascular developmental remodeling.

Paige Snider

Michael Olaopa

Anthony B. Firulli

Simon J. Conway

Cardiovascular Development and the Colonizing Cardiac Neural Crest Lineage

During heart development, cells of the primary and secondary heart field give rise to the myocardial component of the heart. The neural crest and epicardium provide the heart with a considerable amount of nonmyocardial cells that are indispensable for correct heart development. During the past 2 decades, the importance of epicardium-derived cells (EPDCs) in heart formation became increasingly clear. The epicardium is embryologically formed by the outgrowth of proepicardial cells over the naked heart tube. Following epithelial-mesenchymal transformation, EPDCs form the subepicardial mesenchyme and subsequently migrate into the myocardium, and differentiate into smooth muscle cells and fibroblasts. They contribute to the media of the coronary arteries, to the atrioventricular valves, and the fibrous heart skeleton. Furthermore, they are important for the myocardial architecture of the ventricular walls and for the induction of Purkinje fiber formation.Whereas the exact signaling cascades in EPDC migration and function still need to be elucidated, recent research has revealed several factors that are involved in EPDC migration and specialization, and in the cross-talk between EPDCs and other cells during heart development. Among these factors are the Ets transcription factors Ets-1 and Ets-2. New data obtained with lentiviral antisense constructs targeting Ets-1 and Ets-2 specifically in the epicardium indicate that both factors are independently involved in the migratory behavior of EPDCs. Ets-2 seems to be especially important for the migration of EPDCs into the myocardial wall, and to subendocardial positions in the atrioventricular cushions and the trabeculae.With respect to the clinical importance of correct EPDC development, the relation with coronary arteriogenesis has been noted well before. In this review, we also propose a role for EPDCs in cardiac looping, and emphasize their contribution to the development of the valves and myocardial architecture. Lastly, we focus on the congenital heart anomalies that might be caused primarily by an epicardial developmental defect.

Heleen Lie-Venema

Nynke M. S. van den Akker

Noortje A. M. Bax

Elizabeth M. Winter

Saskia Maas

Tuija Kekarainen

Rob C. Hoeben

Marco C. deRuiter

Origin, Fate, and Function of Epicardium-Derived Cells (EPDCs) in Normal and Abnormal Cardiac Development

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The Scientific World Journal

This Issue is now open for submissions.
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The Scientific World Journal

Cardiac Development

Cardiac Development

Articles

A Role for the Cytoskeleton in Heart Looping

The Expanding Role for Retinoid Signaling in Heart Development

Development of the Cardiac Conduction System and the Possible Relation to Predilection Sites of Arrhythmogenesis

Fluid Shear Stress and Inner Curvature Remodeling of the Embryonic Heart. Choosing the Right Lane!

Cardiac Development

Evaluating the Role of Wnt Signal Transduction in Promoting the Development of the Heart

Cardiovascular Development and the Colonizing Cardiac Neural Crest Lineage

Origin, Fate, and Function of Epicardium-Derived Cells (EPDCs) in Normal and Abnormal Cardiac Development