Abstract 199: Dissecting the Shox2-nkx2-5 Antagonistic Mechanism in the Pulmonary Vein Myocardium and Sinoatrial Node
Atrial fibrillation is often triggered by ectopic pacemaking activity in the myocardium sleeves of the pulmonary vein (PV) and systemic venous return. However, the genetic programs that abnormally reinforce pacemaker properties at these sites and how this relates to normal sinoatrial node (SAN) development remain uncharacterized. We have identified a Shox2-Nkx2-5 antagonistic mechanism that primes the pacemaking cell fate in the PV myocardium and SAN in the embryonic stage. Specifically, Shox2 deletion in the Nkx2-5+ domain of the SAN caused sick sinus syndrome, associated with the loss of pacemaker program. Nkx2-5 hypomorphism rescued the requirement for Shox2 for the expression of genes essential for SAN development in Shox2 mutants. Similarly, the pacemaker-like phenotype induced in PV myocardium in Nkx2-5 hypomorphs reverted back to a working myocardial phenotype when Shox2 was simultaneously deleted. Shox2 interacts with Nkx2-5 directly, and a substantial genome wide co-occupancy of Shox2, Nkx2-5, and Tbx5 suggest a balanced transcription output is essential for the pacemaker cell fate determination. Further characterization of mice carrying allelic series of Shox2 and Nkx2-5 revealed an essential role of both Shox2 and Nkx2-5 in maintain the normal development of pulmonary vein myocardium and the structures in the venous pole, suggesting the importance of transcriptional precision of Shox2 and Nkx2-5 and a role of Shox2-Nkx2-5 antagonistic mechanism in integrating the transcriptional accuracy of Shox2 or Nkx2-5.
Author Disclosures: W. Ye: None. J. Wang: None. Y. Song: None. D. Yu: None. C. Sun: None. C. Liu: None. F. Chen: None. Y. Zhang: None. F. Wang: None. R. Harvey: None. L. Schrader: None. J. Martin: None. Y. Chen: None.
This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).
- © 2015 by American Heart Association, Inc.