GATA6 is a key regulator of sinus node (SAN) development. Loss of one Gata6 allele disrupts patterning and size of the SAN. GATA6 plays cell autonomous as well as non-cell autonomous functions in several cell types required for proper SAN development and function. Haploinsufficiency of Gata6 in mice leads to electrophysiological alterations and increases susceptibility to develop arrhythmias. GATA6 is critical for pacemaker cell differentiation and cardiac conduction.
The sinus node (SAN) is the primary pacemaker of the human heart, and abnormalities in its structure or function cause sick sinus syndrome, the most common reason for electronic pacemaker implantation. Here we report that transcription factor GATA6, whose mutations in humans are linked to arrhythmia, is highly expressed in the SAN and its haploinsufficiency in mice results in hypoplastic SANs and rhythm abnormalities. Cell-specific deletion reveals a requirement for GATA6 in various SAN lineages. Mechanistically, GATA6 directly activates key regulators of the SAN genetic program in conduction and nonconduction cells, such as TBX3 and EDN1, respectively. The data identify GATA6 as an important regulator of the SAN and provide a molecular basis for understanding the conduction abnormalities associated with GATA6 mutations in humans. They also suggest that GATA6 may be a potential modifier of the cardiac pacemaker.