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Generation of Murine Cardiac Pacemaker Cell Aggregates Based on ES-Cell-Programming in Combination with Myh6-Promoter-Selection
Published on: February 17, 2015
Targeted mutation reveals essential functions of the homeodomain transcription factor Shox2 in sinoatrial and
Rüdiger J Blaschke1, Nathan D Hahurij, Sanne Kuijper
1Human Genetics, University of Heidelberg, Heidelberg, Germany.
Background:
Identifying molecular pathways regulating the development of pacemaking and coordinated heartbeat is crucial for a comprehensive mechanistic understanding of arrhythmia-related diseases. Elucidation of these pathways has been complicated mainly by an insufficient definition of the developmental structures involved in these processes and the unavailability of animal models specifically targeting the relevant tissues. Here, we report on a highly restricted expression pattern of the homeodomain transcription factor Shox2 in the sinus venosus myocardium, including the sinoatrial nodal region and the venous valves.
Methods And Results:
To investigate its function in vivo, we have generated mouse lines carrying a targeted mutation of the Shox2 gene. Although heterozygous animals did not exhibit obvious defects, homozygosity of the targeted allele led to embryonic lethality at 11.5 to 13.5 dpc. Shox2-/- embryos exhibited severe hypoplasia of the sinus venosus myocardium in the posterior heart field, including the sinoatrial nodal region and venous valves. We furthermore demonstrate aberrant expression of connexin 40 and connexin 43 and the transcription factor Nkx2.5 in vivo specifically within the sinoatrial nodal region and show that Shox2 deficiency interferes with pacemaking function in zebrafish embryos.
Conclusions:
From these results, we postulate a critical function of Shox2 in the recruitment of sinus venosus myocardium comprising the sinoatrial nodal region.
Insights
The homeodomain transcription factor Shox2 is essential for developing the heart's pacemaking region. Shox2 deficiency leads to severe heart defects and embryonic lethality in mice, highlighting its critical role in cardiac development.
Area of Science:
- Developmental Biology
- Cardiovascular Biology
- Genetics
Background:
- Understanding molecular pathways of heart pacemaking is vital for arrhythmia research.
- Developmental structures and targeted models for these processes are poorly defined.
- Shox2, a homeodomain transcription factor, shows restricted expression in the sinus venosus myocardium.
Purpose of the Study:
- To investigate the in vivo function of Shox2 in cardiac development.
- To determine the role of Shox2 in the formation of the sinoatrial nodal region.
Main Methods:
- Generation of Shox2-mutant mouse lines.
- Analysis of embryonic lethality and cardiac morphology in Shox2-/- embryos.
- Assessment of connexin and Nkx2.5 expression.
- Functional studies in zebrafish embryos.
Main Results:
- Shox2-/- embryos exhibit embryonic lethality (11.5-13.5 dpc).
- Severe hypoplasia of the sinus venosus myocardium, including the sinoatrial nodal region and venous valves, was observed.
- Aberrant expression of connexin 40, connexin 43, and Nkx2.5 occurred in the sinoatrial nodal region.
- Shox2 deficiency impaired pacemaking function in zebrafish embryos.
Conclusions:
- Shox2 plays a critical role in the development of the sinus venosus myocardium.
- Shox2 is essential for the recruitment of myocardial tissue forming the sinoatrial nodal region.
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