Developmental Origins of Cardiac Pacemaking Cells

Action potentials generated by pacemaking cells of the Sinoatrial Node control (SAN) rhythmic heartbeat. Despite the importance of pacemaker cells, little is known about their ontogeny or mechanisms of specification and differentiation. We report that SAN pacemaker precursors originate from the right lateral plate mesoderm (LPM), posterior to the known cardiogenic mesoderm. These cells take over pacing function by mid heart‐looping stages, and act as the dominant pacemaker population throughout the morphogenetic changes of heart development. Our mechanistic studies monitoring SAN precursor specification and differentiation demonstrate that when allowed to differentiate in culture SAN precursors uniquely display characteristics consistent with mature SAN pacemaker cells, including sustained beat rate and rhythmicity, selective sensitivity to ion channel blockers, and the ability to pace other myocyte populations. These results suggest that the precursors of the SAN arise from the LPM posterior to the myocytes of the heart tube, that theses cells can differentiate in the absence of other myocyte populations, and that they are specified prior to heart tube formation. Supported by the NIH‐NHLBI.