THE MOLECULAR AND CELLULAR MECHANISMS OF THE HEART PACEMAKER DEVELOPMENT IN VERTEBRATES
A small cohort of a specialized myocytes in the intercaval region constitutes a dominant heart pacemaker, so called sinoatrial node (SAN). The SAN determines proper heart automaticity throughout life in mammals including human. A complicative histological organization, specifc electrophysiology of pacemaker cardiomyocytes and unique genes expression pattern underlie SAN functioning. The development of the SAN starts very early in embryogenesis and continue till late prenatal period. The clarifcation of molecular mechanisms that underlie SAN origin facilitates bio-artifcial pacemakers development, understanding of many cardiovascular diseases including hereditary, developmental or acquired arrhythmias. In addition, the advance in cardiac or somatic cell reprogramming that result from the understanding of SAN embryogenesis promotes cardiac cell-based repair, cell therapy and reversion of pathological remodeling in the heart. To date, a signifcant progress is achieved in the feld of genetic and molecular pathways identifcation that control pacemaker calls nature, govern morphological and functional maturation of the cardiac pacemaker during ontogenesis. In this review a detailed overview of the key transcription factors, morphogenetic signaling molecules (BMP, podoplanin, VEGF, PDGF) and regulatory pathways (Wnt, Wt1, Slit/Robo, RhoA) involved in (epi)genetic control of the pacemaker myocytes progenitors specifcation and diferentiation, as well as in the functional SAN development is presented.