Transcriptional regulation of the cardiac conduction system

Abstract

The rate and rhythm of heart muscle contractions are coordinated by the cardiac conduction system (CCS), a generic term for a collection of different specialized muscular tissues within the heart. The CCS components initiate the electrical impulse at the sinoatrial node, propagate it from atria to ventricles via the atrioventricular node and bundle branches, and distribute it to the ventricular muscle mass via the Purkinje fibre network. The CCS thereby controls the rate and rhythm of alternating contractions of the atria and ventricles. CCS function is well conserved across vertebrates from fish to mammals, although particular specialized aspects of CCS function are found only in endotherms (mammals and birds). The development and homeostasis of the CCS involves transcriptional and regulatory networks that act in an embryonic-stage-dependent, tissue-dependent, and dose-dependent manner. This Review describes emerging data from animal studies, stem cell models, and genome-wide association studies that have provided novel insights into the transcriptional networks underlying CCS formation and function. How these insights can be applied to develop disease models and therapies is also discussed.

Key points

  • The cardiac conduction system (CCS) and atrial and ventricular working myocardium are derived from shared precursor cells that diverge during heart formation owing to localized signalling cues.

  • Differentiation of CCS components is controlled by a network of core cardiac transcription factors and CCS-specific transcription factors; the latter also maintain phenotypic homeostasis of the adult CCS.

  • CCS-specific transcription factors suppress the working myocardial gene programme, maintain embryonic myocardial properties, and activate a pacemaker gene programme.

  • The atrioventricular bundle and bundle branches acquire fast-conducting properties during cardiac development, on top of their pacemaker-like properties.

  • The Purkinje fibre network is derived from the embryonic trabecular chamber myocardium, which acquires fast-conducting properties from the onset of its development.

  • Insights from developmental biology are being applied to develop novel cardiac disease models and additional translational efforts aimed at regeneration of the CCS.

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Fig. 1: Heart development in higher vertebrates.
Fig. 2: Electrical activity of the heart.
Fig. 3: Molecular mechanisms underlying atrioventricular canal and heart chamber development.
Fig. 4: Molecular mechanisms underlying sinoatrial node and sinus horn development.
Fig. 5: Molecular mechanisms underlying atrioventricular bundle and bundle branch development.

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Acknowledgements

V.M.C. is supported by Fondation Leducq grant 14CVD01, Netherlands Heart Foundation grant COBRA3, and CVON grant ConcorGenes. G.J.J.B. is supported by personal grants from the Netherlands Foundation for Scientific Research (ZonMW Veni 016.156.162), the Dutch Heart Foundation (Dr Dekker grant no. 2014T065), and the European Research Council (ERC; Starting Grant no. 714866).

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Glossary terms

NKX2.5

Despite great inconsistency in the literature, in this article we have used the currently accepted nomenclature: thus, NKX2.5 is the protein encoded by the Nkx2-5 gene, with capitalization indicating human (all caps) or mouse (first letter capitalized only) gene names.

MinK–lacZ mice

The MinK gene (now named Kcne1) encodes potassium voltage-gated channel subfamily E member 1, also known as MINK. MINK-deficient mice in which the bacterial lacZ gene has been substituted for the MINK coding region express β-galactosidase under the control of Kcne1 regulatory elements. Thus, β-galactosidase staining in postnatal Kcne1−/− hearts is highly restricted to the sinoatrial node, caudal atrial septum, and proximal cardiac conducting system.

G1N2

The target of a monoclonal antibody (and also the name of the monoclonal antibody itself) initially identified by binding to an extract from the chick ganglion nodosum and later found to bind to the cardiomyocyte subpopulation that develops into the ventricular conduction system, specifically the atrioventricular bundle and bundle branches.

Mef2c–AHF-enhancer

An intronic regulatory element from the mouse Mef2c gene (encoding myocyte enhancer factor 2C) identified in transgenic mice. When used to drive either lacZ or cre expression, this enhancer was found to be active specifically in the anterior second heart field (AHF) during early cardiogenesis and was termed the Mef2c–AHF-enhancer.

MYH6-promoter-based antibiotic selection

In this technique, a plasmid containing an antibiotic selection cassette (an antibiotic resistance gene controlled by the MYH6 promoter) is inserted into the stem cell population of interest. Administration of this antibiotic during T-box transcription factor TBX3-induced cardiac differentiation results in enrichment of pacemaker-like cells.

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van Eif, V.W.W., Devalla, H.D., Boink, G.J.J. et al. Transcriptional regulation of the cardiac conduction system. Nat Rev Cardiol 15, 617–630 (2018). https://doi.org/10.1038/s41569-018-0031-y

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