Molecular pathways involving the homeodomain transcription factor SHOX2 control the development and function of the native cardiac pacemaker in animal models and mouse embryonic stem cells. Studies in SHOX2 knockout mice have revealed a crucial role for SHOX2 in early cardiac formation, particularly in sinoatrial node development and specification. Furthermore, it was shown that in zebrafish embryos the loss of SHOX2 leads to substantial impairment in pacemaker function, with severe bradycardia (slow and irregular heartbeat). A functional link between the expression of the homeodomain transcription factor SHOX2, the development of the sinoatrial node and arrhythmogenic phenotypes has been established. Developing a mechanistic classification of atrial arrhythmias based on health modifiers like genetic susceptibility is essential to improve personalized prevention and management of those diseases. Modelling atrial arrhythmias with genotype-guided approaches using iPSCs will improve our understanding of the molecular mechanisms by which genomic variations cause disease. These approaches provide preclinical models for the selection of novel therapeutic targets, paving the way to personalized medicine.
SHOX2