LAUSR

Cardiac Pacemaker Cells (CPCs) rhythmically initiate the electrical impulses that drive heart contractions. Paradoxically, CPCs display the highest rate of spontaneous depolarization in the heart despite being subjected to unfavorable electrochemical conditions that should theoretically suppress their activity. How CPCs overcome such barriers remains a fundamentally unresolved topic in our understanding of cardiac electrophysiology. To address this, we have used computational modeling, high resolution in vivo imaging, and direct genetic manipulation of CPCs to examined the developmental processes that coordinate CPC electrical integration into the embryonic heart. Through these studies we have uncovered a series of previously unrecognized cytoarchitectural patterning events that are critical for CPC function. Specifically, we have identified that CPCs uniquely internalize their adherens junction complexes during early cardiac morphogenesis. As a result, CPCs adopt physical attributes, such as small cell size, and electrical characteristics, including poor gap junctional coupling, that are highly beneficial for maintenance of their excitability. Importantly, our data also demonstrate that ectopic adherens junction formation severely perturbs CPC function in a force dependent manner. Thus, these data highlight that regulation of cell-cell interactions controls the basic structural parameters needed to support CPC activity in the heart and that local cellular mechanics should be a design consideration as cellular-based therapeutics for the correction of CPC dysfunction become increasingly feasible.