Gene regulatory networks for the development and evolution of the chordate heart: Figure 1.

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Gene regulatory networks consisting of subcircuits of transcription factors and intercellular signaling molecules are key to an understanding of the complex mechanisms of animal development and evolution (Davidson and Erwin 2006). One of the most intensively studied genetic networks is that for the formation of the animal heart. Since the discovery of the “tinman” gene (Bodmer 1993) and its vertebrate homolog, Nkx2.5 (Lyons et al. 1995), many genes have been found to be involved in heart development in a wide range of animals, from insects to mammals. Actually, it is well established that a gene circuit consisting of GATA, Nkx, and Hand is evolutionarily highly conserved. This gene circuit constitutes a “kernel,” which is evolutionarily inflexible and performs essential regulatory functions in building a body part (Davidson and Erwin 2006). Analyses of vertebrate heart development revealed that the differentiation of cardiac muscle cells and morphogenesis of the heart are governed by this heart kernel gene regulatory network (Cripps and Olson 2002; Harvey 2002; Buckingham et al. 2005). An important question to be answered about the formation of the heart in vertebrates and other chordates is how this kernel is turned on at the earliest stages of the heart cell specification process to establish the heart field. Another intriguing question in chordate heart formation is how the dualor multichambered heart of vertebrates evolved. It is generally believed that the ancestral chordate resembled the present-day ascidian tadpole. The morphogenetic movement of heart precursor cells during ascidian larval development and metamorphosis is reminiscent of those in vertebrates (Davidson and Levine 2003). However, the ascidian tube-like heart lacks chambers. The innovation of the chambered heart was a key event in vertebrate evolution, because the chambered heart generates one-way blood flow with high pressure, a critical requirement for the efficient blood supply of large-body vertebrates. In this issue of Genes & Development, Davidson et al. (2006) addressed these questions by examining the function of an Ets-containing transcription factor in the tunicate, Ciona intestinalis. They found that Ci-Ets1/2 (because this is one of two Ciona orthologs for vertebrate Ets1 and Ets2 and Drosophila pointed, it was originally called Ci-ets/pointed2) (Yagi et al. 2003) establishes the heart field, probably through an FGF signal acting downstream from Ci-Mesp, a basic helix–loop–helix transcription factor gene required for the initial specification of heart precursor cells (Satou et al. 2004). Targeted inhibition of Ci-Ets1/2 or FGF receptor function blocks heart formation. Moreover, targeted expression of a constitutively active Ci-Ets1/2 causes the expansion of the heart field by forced recruitment of larval tail muscle cells that express Ci-Mesp. Interestingly, this heart field expansion, evoked by the subtle alteration of the heart genetic program, caused a morphological change—that is, to a heart with two compartments.