Cardiogenesis and the Regulation of Cardiac-Specific Gene Expression Jau-Nian Chen, PhD a , Douglas B. Cowan, PhD b , John D. Mably, PhD c, * a University of California Los Angeles, Los Angeles, CA, USA b Children’s Hospital Boston, Boston, MA, USA c Massachusetts General Hospital, Boston, MA, USA Development and maturation of the embryonic vertebrate heart is an exquisitely conducted ensemble of cell movements, interactions, and morphologic transformations. The genetic orchestration of these events is precise and can be reduced to dissonance by the loss of a single component in this process. Proper heart morphogenesis is important to normal embry- onic development because the heart is the first organ formed. All subsequent events depend on the ability of the heart to supply oxygen and nutrients to fulfill the metabolic requirements of the organism. Abnor- malities in the formation of the heart often lead to abnormal function and embryonic lethality or may manifest later in life, causing severe health issues. Cardiac defects are among the most common birth defects, estimated at an incidence of 6 in 1000 live births, with an even higher frequency in spontane- ously aborted pregnancies [1]. Much of our under- standing of the mechanisms and pathways regulating cardiogenesis evolved from studies in model systems, notably the mouse, chick, fly, frog, and zebrafish. This article outlines the molecular events and mecha- nisms regulating heart formation, focusing on recently identified members of the cardiogenic reper- toire [2–5]. Early morphogenesis Adult vertebrate hearts may vary greatly in their overall structures, but the morphogenic processes that shape the embryonic hearts of vertebrate species are shared. In brief, vertebrate heart formation begins when a bilaterally symmetric population of meso- dermal cells in the anterior lateral plate becomes committed to a cardiac fate in response to inductive signals from the adjacent endoderm [6]. Migration of these cardiogenic cells to the midline of the embryo results in the formation of a linear heart tube (the primitive heart tube). Cardiomyocytes adopt an atrial or a ventricular cell fate during differentiation of the primitive heart tube along the anterior-posterior axis, although studies in zebrafish suggest this specifica- tion occurs earlier, prior even to heart tube formation [7]. The atrium and ventricle then undergo a right- ward looping (cardiac looping) that is essential for alignment of the inflow and outflow tracts and for orienting the atrial and ventricular chambers [8]. Data accumulated from studies over the last decade suggest that in addition to these morphogenic events, the genetic circuits critical for heart development also are conserved across species [9]. This complex crosstalk between tissues is essen- tial for cardiogenesis, in part contingent on the ex- pression of an extensive assemblage of transcription factors. Through precise temporal and spatial regu- lation, the expression of these factors leads uncom- mitted cells to enter the cardiac lineage. In the fruit fly, Drosophila melanogaster, the activity of the homeobox gene tinman is required for the formation 1551-7136/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.hfc.2005.03.002 heartfailure.theclinics.com * Corresponding author. Cardiovascular Research Cen- ter, Massachusetts General Hospital and the Department of Medicine, Harvard Medical School, 149 13th Street, Boston, MA 02129. E-mail address: jmably@partners.org (J.D. Mably). Heart Failure Clin 1 (2005) 157 – 170