ArticleThe Journal of biological chemistry2015
The short stature homeobox 2 (Shox2)-bone morphogenetic protein (BMP) pathway regulates dorsal mesenchymal protrusion development and its temporary function as a pacemaker during cardiogenesis.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 32 citations in OpenAlex.
- Cardiac conduction system malformations in heterotaxy result from dysregulated Pitx2 expression.JCI insight · 2026Article
- Screening and Identification of BMP5 as a Key Regulatory Gene for hPSCs Transcardiomyocyte Differentiation.Stem cells international · 2026Article
- The Neglected Internodal Tract-A Cardiac Conduction System Structure Homologous to the Development and Regulation of the Sinoatrial Node.Reviews in cardiovascular medicine · 2025Review
- Evaluation of the Potential Targets of Shenxian-Shengmai Oral Liquid in Treating Sick Sinus Syndrome Based on Network Pharmacology and Molecular Docking.Food science & nutrition · 2024Article
- Segregation of morphogenetic regulatory function of Shox2 from its cell fate guardian role in sinoatrial node development.Communications 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
- Sox9 Expression in the Second Heart Field; A Morphological Assessment of the Importance to Cardiac Development with Emphasis on Atrioventricular Septation.Journal of cardiovascular development and disease · 2022Article
- A BMP4-p38 MAPK signaling axis controls ISL1 protein stability and activity during cardiogenesis.Stem cell reports · 2021Article
- The Transcription Factor Shox2 Shapes Neuron Firing Properties and Suppresses Seizures by Regulation of Key Ion Channels in Thalamocortical Neurons.Cerebral cortex (New York, N.Y. : 1991) · 2021Article
- Fluorescent PSC-Derived Cardiomyocyte Reporter Lines: Generation Approaches and Their Applications in Cardiovascular Medicine.Biology · 2020Review
- Conjugated activation of myocardial-specific transcription of Gja5 by a pair of Nkx2-5-Shox2 co-responsive elements.Developmental biology · 2020Article
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- Bone morphogenetic protein 4 promotes the differentiation of Tbx18-positive epicardial progenitor cells to pacemaker-like cells.Experimental and therapeutic medicine · 2019Article
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- On the Evolution of the Cardiac Pacemaker.Journal of cardiovascular development and disease · 2017Review
- Genetic Regulation of Sinoatrial Node Development and Pacemaker Program in the Venous Pole.Journal of cardiovascular development and disease · 2015Article
- New Approaches to Biological Pacemakers: Links to Sinoatrial Node Development.Trends in molecular medicine · 2015Review
- Diagnosis of Lung Cancer by SHOX2 Gene Methylation Assay.Molecular diagnosis & therapy · 2015Review
- Reply to Kelder et al.: Does the dorsal mesenchymal protrusion act as a temporary pacemaker during heart development?The Journal of biological chemistry · 2015Article
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13 authors at 1 institution in 1 country.
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Abstract
The atrioventricular (AV) junction plays a critical role in chamber septation and transmission of cardiac conduction pulses. It consists of structures that develop from embryonic dorsal mesenchymal protrusion (DMP) and the embryonic AV canal. Despite extensive studies on AV junction development, the genetic regulation of DMP development remains poorly understood. In this study we present evidence that Shox2 is expressed in the developing DMP. Intriguingly, this Shox2-expressing domain possesses a pacemaker-specific genetic profile including Hcn4 and Tbx3. This genetic profile leads to nodal-like electrophysiological properties, which is gradually silenced as the AV node becomes matured. Phenotypic analyses of Shox2(-/-) mice revealed a hypoplastic and defectively differentiated DMP, likely attributed to increased apoptosis, accompanied by dramatically reduced expression of Bmp4 and Hcn4, ectopic activation of Cx40, and an aberrant pattern of action potentials. Interestingly, conditional deletion of Bmp4 or inhibition of BMP signaling by overexpression of Noggin using a Shox2-Cre allele led to a similar DMP hypoplasia and down-regulation of Hcn4, whereas activation of a transgenic Bmp4 allele in Shox2(-/-) background attenuated DMP defects. Moreover, the lack of Hcn4 expression in the DMP of mice carrying Smad4 conditional deletion and direct binding of pSmad1/5/8 to the Hcn4 regulatory region further confirm the Shox2-BMP genetic cascade in the regulation of DMP development. Our results reveal that Shox2 regulates DMP fate and development by controlling BMP signaling through the Smad-dependent pathway to drive tissue growth and to induce Hcn4 expression and suggest a temporal pacemaking function for the DMP during early cardiogenesis.
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