Setting the pace: Tbx3 and Tbx18 in cardiac conduction system development.

A vexing problem for clinicians in the management of children and adults with congenital heart disease is the management of the accompanying arrhythmias. In the recent decade, the mutational spectrum associated with human congenital heart disease has begun to come into focus.1 The number of distinct genes implicated in human congenital heart disease is considerable, and a large portion of mutated genes encode transcription factors. Autosomal dominant mutations in NKX2.5 associate with primarily atrial septal defects, but importantly these defects are distinguished by the presence of atrioventricular nodal defects including heart block. The Holt–Oram syndrome, or heart–hand syndrome, arises from dominant mutations in Tbx5, a member of the brachyury family of transcription factors and is also associated with the development of atrioventricular nodal disease. Further investigation of these genes using mouse genetic models has begun to refine the detailed program required for development of specific components of the cardiac conduction system. The mammalian cardiac conduction system is composed of the sinoatrial (SA) node, the atrioventricular node, the His bundle, the left and right bundle branches, and the ventricular Purkinje fibers. For many of these components, transcriptional regulators have been identified that are critical for their proper development or maintenance (see Figure). Nkx2.5 is required for the development and maintenance of the atrioventricular node.2 In addition, the development of the atrioventicular node is also dependent on Tbx5 and Id2, whereas the distal ventricular conduction system requires Id2 and HOP.3,4 The precise delineation and maintenance of the conduction system likely requires more than just these factors. In mammals, the SA node serves as the dominant pacemaker from its position in the right atrium near the junction with the superior vena cava. The SA node is nonuniform in cell content and function. Early morphological studies described 3 cell types: nodal, intermediate, and elongated cells where nodal cells were thought to drive the pacemaker. Nodal cells were defined by their small shape and ovoid morphology. The mammalian SA node is also unique in having a head region and a tail or cauda yielding a comet-shaped structure. The cauda was observed to have nearly all nodal cells with fewer intermediate and elongated cells.5 Previous work by Blaschke et al suggested the importance of the homeodomain transcription factor Shox2 in the development of the SA node.6 The recent work of Christoffels and colleagues has advanced our understanding of the SA node by clarifying the essential role of the transcription factor Tbx3 in specifying atrial versus SA node cells.7 Tbx3 is thought to function as a transcriptional repressor to suppress atrial myocyte phenotype.8 Mice lacking Tbx3 die during embryogenesis between embryonic day (E)11.5 and E14. Tbx3-null mice develop multiple abnormalities including limb malformation and failure to develop mammary glands. Therefore, Tbx activity is not unique to the developing heart and conduction system. However, within the heart Tbx3 expression is required for normal size and function of the SA node. Critically, ectopic Tbx3 expression within the atria is sufficient to induce ectopic pacemaker sites associated with suppression of normal atrial gene expression and induction of Hcn4. The mechanism by which suppression of atrial myocyte gene expression couples to promote the unique gene expression profile within the SA node is not clear. In this issue of Circulation Research, Wiese et al further define the complexity of SA node development by demonstrating that Tbx18 also contributes significantly by driving specification of the head and tail components of the SA node.9 The largest portion of the SA node is the head region, and Wiese et al demonstrate that the loss of Tbx18 is required for normal formation of the SA node head region.9 The authors first demonstrated that the large SA node head differs in its gene expression profile compared to the SA node tail. Specifically, the head expressed Tbx18 and Hcn4 and lacked expression of NKX2.5. In contrast, the tail lacked Tbx18 expression and demonstrated higher levels of Hcn4 and low levels of NKX2.5 expression. Normally in the mouse, the SA node head quadruples in size between E12.5 and E14.5. In Tbx18-deficient embryos, the tail portion of the SA node developed at E12.5, but the head region was absent at this point. Two days later, the SA node head region remained largely unformed. This absence was not associated with a reduction in cell proliferation or an increase in apoptosis. In addition, the expression of Shox2 was unaffected in Tbx18deficient embryos, suggesting that Shox2 is upstream of Tbx18 or in a parallel pathway in the transcriptional regulation of SA node specification. It will be of interest to determine the pattern of expression of Tbx3 and Tbx18 in Shox2-deficient embryos. The origin of the cardiac conduction system, especially the SA node, has been uncertain. Conduction system cells may develop directly from mesodermal precursors that migrate into the heart and then differentiate into conduction system. The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Section of Cardiology, University of Chicago, Ill. Correspondence to Elizabeth M. McNally, 5841 S Maryland, MC6088, Chicago, IL 60637. E-mail [email protected] (Circ Res. 2009;104:285-287.) © 2009 American Heart Association, Inc.