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Published on: September 23, 2014
HCN4 dynamically marks the first heart field and conduction system precursors
Xingqun Liang1,2, Gang Wang1, Lizhu Lin1
1Skaggs School of Pharmacy and Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
Insights
HCN4 is identified as a novel marker for the first heart field and cardiac conduction system (CCS) precursors. This discovery aids in understanding heart development and potentially in developing biological pacemakers.
Area of Science:
- Cardiovascular Research
- Developmental Biology
- Molecular Cardiology
Background:
- Cardiac arrhythmia, a major cause of death, often stems from cardiac conduction system (CCS) abnormalities.
- Identifying specific markers for the first heart field and CCS lineages is crucial for disease modeling and biological pacemaker development.
Purpose of the Study:
- To investigate HCN4 as a marker for the first heart field and CCS precursors.
- To elucidate the contributions of first and second heart lineages to the CCS.
Main Methods:
- Generation of HCN4CreERT2, -nuclear LacZ, and -H2BGFP mouse lines.
- Examination of HCN4 expression via immunostaining and reporter gene expression.
- Lineage tracing using various Cre-driver mouse lines (HCN4CreERT2, Isl1Cre, Nkx2.5Cre, Tbx18Cre) and coimmunostaining with CCS markers.
Main Results:
- HCN4 marks the first heart field at cardiac crescent stages.
- HCN4 expression delineates distinct CCS precursors throughout embryonic development, marking the entire CCS by late fetal stages.
- HCN4 expression was also observed in specific subsets of endothelium during development.
Conclusions:
- HCN4 serves as a valuable marker for the first heart field and CCS development.
- Findings provide insight into the contributions of different heart lineages to the CCS.
- HCN4, combined with other markers, can optimize protocols for generating and isolating specific conduction system precursors.
Rationale:
To date, there has been no specific marker of the first heart field to facilitate understanding of contributions of the first heart field to cardiac lineages. Cardiac arrhythmia is a leading cause of death, often resulting from abnormalities in the cardiac conduction system (CCS). Understanding origins and identifying markers of CCS lineages are essential steps toward modeling diseases of the CCS and for development of biological pacemakers.
Objective:
To investigate HCN4 as a marker for the first heart field and for precursors of distinct components of the CCS, and to gain insight into contributions of first and second heart lineages to the CCS.
Methods And Results:
HCN4CreERT2, -nuclear LacZ, and -H2BGFP mouse lines were generated. HCN4 expression was examined by means of immunostaining with HCN4 antibody and reporter gene expression. Lineage studies were performed using HCN4CreERT2, Isl1Cre, Nkx2.5Cre, and Tbx18Cre, coupled to coimmunostaining with CCS markers. Results demonstrated that, at cardiac crescent stages, HCN4 marks the first heart field, with HCN4CreERT2 allowing assessment of cell fates adopted by first heart field myocytes. Throughout embryonic development, HCN4 expression marked distinct CCS precursors at distinct stages, marking the entire CCS by late fetal stages. We also noted expression of HCN4 in distinct subsets of endothelium at specific developmental stages.
Conclusions:
This study provides insight into contributions of first and second heart lineages to the CCS and highlights the potential use of HCN4 in conjunction with other markers for optimization of protocols for generation and isolation of specific conduction system precursors.
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