Lineage tracing has shown that the different regions of the four-chambered heart of mammalian embryos derive from molecularly distinct precursor pools in a spatially and temporally tightly controlled manner. Cells of the first heart field differentiate early and form the linear heart tube of headfold-stage embryos, the future left ventricle. The right ventricle, atria, and outflow tract derive from the second heart field by recruitment and delayed local myocardial differentiation. Finally, Tbx18(+) precursors are added at the posterior cardiac pole after the chambers have been formed to generate the myocardialized aspects of the mature venous return system, including the intrapericardial parts of the caval veins and the sinoatrial node. The elongation of the linear heart tube by second heart field-derived cells requires the maintenance of highly proliferative precursor pools by a number of signaling pathways, including sonic hedgehog, fibroblast growth factor, and canonical Wnt. The molecular circuits that operate during the addition of the most posterior components from Tbx18(+) progenitors have remained elusive. It has emerged that at least one of the pathways required for proliferation of second heart field progenitors, canonical Wnt signaling, also operates in a subset of Tbx18(+) cells for formation of myocardialized caval veins. This argues for both conserved and specific regulatory modules mediating the polar extension of the cardiac tube during embryogenesis.
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