Important factors in the specification of pacemaker cells in the SAN and atrial working myocardium. SAN cells arise from a Tbx18+Nkx2.5− mesenchymal progenitor population located adjacent to the Nkx2.5+ posterior heart tube myocytes. Tbx18 is the main driving factors of myocardial differentiation in the mesenchymal progenitors. It delineates the SAN primordium by competing with Tbx5 and functionally repressing atrial differentiation factors such as Gata4, Nkx2.5, and Nppa. Shox2 inhibits Nkx2.5 expression, activates Tbx3 and interacts with Isl1. Shox2 is a direct target of laterality factor Pitx2 and is inhibited in the left compartments of the developing heart. Tbx3 is the main factor to directly or indirectly activate pacemaker-specific factors. Tbx5 interacts with Gata4 and Nkx2.5 to initiate working myocardial cell differentiation. Tbx5 represses Shox2 in the working myocardium. Nkx2.5 is the main determining factor for chamber myocardial cells and activates working myocardium-specific factors. The transcription factor network leads to the establishment of specific gene expression signatures. The SAN is characterised by the high expression of Tbx3, Shox2, Isl1, Bmp4, Hcn4, Cacna1g, Cx30.2 (mouse), and Cx45, corresponding with the low expression or absence of Cx40, Cx43, and Scn5a in embryos and adults. The working myocardium shows a contrary expression pattern, with the high expression of Cx40, Cx43, Scn5a, and Nppa corresponding to low or absent expression of Cx30.2 (mouse), Cx45, and Hcn4.
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