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Abstract

See related article, pages 1340–1349 In this issue of Circulation Research , Bakker et al1 report that the T-box transcription factor Tbx3 is required for development of the mouse atrioventricular conduction system. This study adds to the increasingly complex roles for T-box genes in the regulation of cell lineage maturation and proliferation in the developing heart. Previous studies from this same group have implicated Tbx3 in control of mouse sinoatrial node development and pacemaker activity.2 A closely related factor Tbx2 also contributes to atrioventricular (AV) canal specification by repressing genes expressed in the chamber myocardium.3,4 Mutations in human TBX5 cause Holt–Oram syndrome, which includes conduction system disease, and mice with heterozygous mutations in Tbx5 develop progressive AV block and other conduction anomalies.5–7 Additional T-box factors including Tbx1, Tbx20, and Tbx18 are expressed in distinct compartments of the heart and have critical functions in cardiac cell lineage maturation, proliferation, and morphogenesis.8 It is becoming increasingly apparent that multiple T-box transcription factors are important regulators of conduction system differentiation and patterning while also contributing to many other aspects of heart cell lineage development and morphogenesis. Bakker et al1 report that Tbx3 is required for maturation of the atrioventricular conduction system based on loss of function studies in mice. Mice lacking Tbx3 do not survive past embryonic day (E)14.5 and exhibit abnormal gene expression in conduction system progenitor cells, as well as severe structural malformations, including double outlet right ventricle and ventricular septal defects. Particular attention was paid to the crest of the interventricular septum, where the AV bundle components of the central conduction system will develop. In normal mice, the myocytes in the crest of the interventricular septum diversify from the rest of the septum myocardium with increased expression of Tbx3 , Tbx5 , …