A common Shox2–nkx2-5 antagonistic mechanism primes the pacemaker cell fate in the pulmonary vein myocardium and sinoatrial node

Wenduo Ye, Jun Wang, Yingnan Song, Diankun Yu, Cheng Sun, Chao Liu, Fading Chen, Yanding Zhang, Fen Wang, Richard P. Harvey, Laura Schrader, James F. Martin, Yi Ping Chen

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

In humans, atrial fibrillation is often triggered by ectopic pacemaking activity in the myocardium sleeves of the pulmonary vein (PV) and systemic venous return. The genetic programs that abnormally reinforce pacemaker properties at these sites and how this relates to normal sinoatrial node (SAN) development remain uncharacterized. It was noted previously that Nkx2-5, which is expressed in the PV myocardium and reinforces a chamber-like myocardial identity in the PV, is lacking in the SAN. Herewe present evidence that in mice Shox2 antagonizes the transcriptional output of Nkx2-5 in thePVmyocardium and in a functional Nkx2-5+ domain within the SAN to determine cell fate. Shox2 deletion in the Nkx2-5+ domain of the SAN caused sick sinus syndrome, associated with the loss of the pacemaker program. Explanted Shox2+ cells from the embryonic PV myocardium exhibited pacemaker characteristics including node-like electrophysiological properties and the capability to pace surrounding Shox2 cells. Shox2 deletion led to Hcn4 ablation in the developing PV myocardium. Nkx2- 5 hypomorphismrescued the requirement for Shox2 for the expression of genes essential for SAN development in Shox2 mutants. Similarly, the pacemaker-like phenotype induced in thePVmyocardium in Nkx2- 5 hypomorphs reverted back to a working myocardial phenotype when Shox2 was simultaneously deleted. A similar mechanism is also adopted in differentiated embryoid bodies. We found that Shox2 interacts with Nkx2-5 directly, and discovered a substantial genomewide co-occupancy of Shox2, Nkx2-5 and Tbx5, further supporting a pivotal role for Shox2 in the core myogenic program orchestrating venous pole and pacemaker development.

Original languageEnglish (US)
Pages (from-to)2521-2532
Number of pages12
JournalDevelopment (Cambridge)
Volume142
Issue number14
DOIs
StatePublished - Jul 15 2015
Externally publishedYes

Keywords

  • Atrial fibrillation
  • Cell fate
  • Human
  • Mouse
  • Nkx2-5
  • Pulmonary vein
  • Shox2
  • Sinoatrial node

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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