PROJECT SUMMARY Atrial fibrillation (AF) is the leading cause of stroke and a major cause of morbidity and mortality in the US. AF is due to both inherited and acquired factors. Genome-wide association studies have identified ERBB4 as a candidate susceptibility gene for AF. Acquired conditions, such as aging, hypertension, and heart failure, are known to cause electrical and structural changes in the left atrium (LA) in a process known as remodeling that predisposes to AF. Our data show that left atrial ERBB4 levels are reduced in patients with AF. We have also shown that ErbB4 is downregulated in heart disease mouse models. To study the role of ErbB4 in both atrial electrical development and in acquired AF mechanisms, we have generated mouse models that have reduced ErbB4 expression during development or acquired during adulthood. Both model systems show an important dependency of correct ErbB4 gene dosage in the maintenance of normal atrial electrophysiology.