ArticleDevelopment (Cambridge, England)2015
A common Shox2-Nkx2-5 antagonistic mechanism primes the pacemaker cell fate in the pulmonary vein myocardium and sinoatrial node.
Article in Development (Cambridge, England), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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Who cites it
67 citing papers in PubMed, 99 citations in OpenAlex.
- The cardiac conduction system: development, function and therapeutic targets.Nature reviews. Cardiology · 2026Review
- Cardiac conduction system malformations in heterotaxy result from dysregulated Pitx2 expression.JCI insight · 2026Article
- PITX2 dosage-dependent changes in pacemaker cell state underlie sinus node dysfunction and atrial arrhythmias.Nature communications · 2025Article
- The Neglected Internodal Tract-A Cardiac Conduction System Structure Homologous to the Development and Regulation of the Sinoatrial Node.Reviews in cardiovascular medicine · 2025Review
- A gene desert required for regulatory control of pleiotropic Shox2 expression and embryonic survival.Nature communications · 2024Article
- A new paradigm for generating high-quality cardiac pacemaker cells from mouse pluripotent stem cells.Signal transduction and targeted therapy · 2024Article
- Transcriptional regulation of the postnatal cardiac conduction system heterogeneity.Nature communications · 2024Article
- TBX3 transfection and nodal signal pathway inhibition promote differentiation of adipose mesenchymal stem cell to cardiac pacemaker-like cells.Stem cell research & therapy · 2024Article
- Segregation of morphogenetic regulatory function of Shox2 from its cell fate guardian role in sinoatrial node development.Communications biology · 2024Article
- Development of the Cardiac Conduction System.Advances in experimental medicine and biology · 2024Article
- The method of sinus node-like pacemaker cells from human induced pluripotent stem cells by BMP and Wnt signaling.Cell biology and toxicology · 2023Article
- Knockout of the Cardiac Transcription Factor NKX2-5 Results in Stem Cell-Derived Cardiac Cells with Typical Purkinje Cell-like Signal Transduction and Extracellular Matrix Formation.International journal of molecular sciences · 2023Article
- Local tissue mechanics control cardiac pacemaker cell embryonic patterning.Life science alliance · 2023Article
- Genetics of sinoatrial node function and heart rate disorders.Disease models & mechanisms · 2023Review
- Article
- Global chromatin landscapes identify candidate noncoding modifiers of cardiac rhythm.The Journal of clinical investigation · 2023Article
- Novel Insights into the Sinoatrial Node in Single-Cell RNA Sequencing: From Developmental Biology to Physiological Function.Journal of cardiovascular development and disease · 2022Review
- α1-adrenergic receptors accompanied by GATA4 expression are related to proarrhythmic conduction and automaticity in rat interatrial septum.Journal of physiology and biochemistry · 2022Article
- Improved Generation of Human Induced Pluripotent Stem Cell-Derived Cardiac Pacemaker Cells Using Novel Differentiation Protocols.International journal of molecular sciences · 2022Article
- A dualiScience · 2022Article
7 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 5 institutions in 3 countries.
Funding
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. Here we present evidence that in mice Shox2 antagonizes the transcriptional output of Nkx2-5 in the PV myocardium 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 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 the PV myocardium 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 genome-wide 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.