The Molecular and Cellular Mechanisms of Heart Pacemaker Development in Vertebrates

– A small group of specialized myocardial cells constitutes a natural dominant heart pacemaker in the so-called sinoatrial node (SAN). The SAN determines proper heart automaticity throughout life in animals, including humans. The heart pacemaker is characterized by specific histological organization and unique pattern of gene expression, defining the electrophysiological phenotype of constituent cardiomyocytes. The SAN development starts very early in embryogenesis and continues until the late prenatal period. The clarification of the origin of the heart pacemaker and molecular mechanisms controlling its development promotes the elaboration of bio-artificial pacemakers and understanding of causes for many cardiovascular diseases, including hereditary, developmental or acquired arrhythmias. The investigation of SAN embryogenesis facilitates the solution of reprogramming problem for cardiomyocytes or somatic cells designed for cellular therapy of cardiovascular diseases and reversion of pathological heart remodeling. To date, significant progress has been achieved in the field of identifying genetic and molecular pathways that control the pacemaker cells' nature and govern morphological and functional maturation of the dominant cardiac pacemaker during ontogenesis. This review provides the information on the key transcription factors and molecular regulatory cascades (BMP, Wnt, Wt1, Slit/Robo, RhoA, podoplanin, VEGF, and PDGF) involved in (epi)genetic control of the pacemaker myocyte progenitors and determination of their electrophysiological phenotypes.