Abstract
The cardiac conduction system (CCS) transmits electrical activity from the atria to the ventricles to coordinate heartbeats. Atrioventricular conduction diseases are often associated with defects in the central ventricular conduction system comprising the atrioventricular bundle (AVB) and right and left branches (BBs). Conducting and contractile working myocytes share common cardiomyogenic progenitors, however the time at which the CCS lineage becomes specified is unclear. In order to study the fate and the contribution to the CCS of cardiomyocytes during early heart tube formation, we performed a genetic lineage analysis using a Sma-CreERT2 mouse line. Lineage tracing experiments reveal a sequential contribution of early Sma expressing cardiomyocytes to different cardiac compartments, labeling at embryonic day (E) 7.5 giving rise to the interventricular septum and apical left ventricular myocardium. Early Sma expressing cardiomyocytes contribute to the AVB, BBs and left ventricular Purkinje fibers. Clonal analysis using the R26-confetti reporter mouse crossed with Sma-CreERT2 demonstrates that early Sma expressing cardiomyocytes include cells exclusively fated to give rise to the AVB. In contrast, lineage segregation is still ongoing for the BBs at E7.5. Overall this study highlights the early segregation of the central ventricular conduction system lineage within cardiomyocytes at the onset of heart tube formation.
Highlights
The cardiac conduction system (CCS) generates and propagates electrical impulses to coordinate atrial and ventricular contraction
This conclusion is based on the analysis of mouse mutants and genetic tracing showing that the LIM homeodomain transcription factor Isl1 is selectively expressed in SHF cells, which will form the outflow tract, right ventricle, right atria, and a portion of cells of the left ventricle and left atria
This conclusion is in agreement with data from early fate mapping of the cardiac tube in chicks showing that the primordium of the interventricular septum appears at the site of ventral fusion of bilateral cardiac primordia [27,28]
Summary
The cardiac conduction system (CCS) generates and propagates electrical impulses to coordinate atrial and ventricular contraction. A clonal retrospective analysis combined with a Connexin Cx40-GFP reporter mouse line revealed that the VCS is comprised of cells derived from two progenitor cell lineages that contribute to either the right Purkinje fiber network or left BB, likely corresponding to contributions of first and second heart field progenitor cells [12] Both lineages were found to participate in the formation of the AV conduction system including the AVN, AVB, and right BB. The contribution of the Hcn expressing cells to the CCS varies depending on the time of Cre induction, the entire CCS only being labelled after induction at late fetal stages These genetic tracing analyses suggest that the central VCS is derived mainly from the FHF, the timing of the lineage segregation remains unclear. Clonal analysis using the R26-confetti reporter mouse crossed with Sma-CreERT2, highlights the early segregation of the central VCS lineage within SMA positive cells
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