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.

Embryonic Tbx3+ cardiomyocytes form the mature cardiac conduction system by progressive fate restriction

“…Disease modeling in patientspecific induced pacemaker cells seems possible in the near future. Moreover, there is a great interest in the development of biological pacemakers by reprogramming resident cells of the heart (Boink et al, 2015;Cingolani et al, 2018;Rosen et al, 2011;van Eif et al, 2018). Our data indicate that with both approaches, early onset and maintenance of Tbx3 expression at the right level is a prerequisite to obtain and maintain induced pacemaker disease models or biological pacemakers for regenerative purposes.…”

“…Dysfunction of the cardiac conduction system (CCS) due to gene mutations, congenital defects, damage after surgery or degenerative disease leads to severe arrhythmias (Baruteau et al, 2015;Park and Fishman, 2011;Wolf and Berul, 2006). Defining the developmental origin and mode of the CCS components is a crucial step towards understanding the etiology of conduction diseases and to pave the way for the development of regenerative strategies (Boink et al, 2015;Cingolani et al, 2018;Rosen et al, 2011;van Eif et al, 2018).…”

“…CCS cells in the different components have unique functional properties, yet they also share properties, including spontaneous activity (or automaticity) (Dobrzynski et al, 2013;Mangoni and Nargeot, 2008;van Eif et al, 2018). Tbx3 is specifically expressed in all components of the adult CCS, except for the PFN (Hoogaars et al, 2004).…”

Reptiles as a Model System to Study Heart Development

“…Figure 3 shows key elements of this network, the genes of which have been investigated in reptiles (text in red). The sinuatrial junction, which harbors the dom-inant pacemaker, expresses Tbx3 and Bmp2 together with Isl1, a transcription factor that acts upstream of Tbx3 (Hoffmann et al 2013;Vedantham et al 2015;Burkhard et al 2017;Jensen et al 2017b;van Eif et al 2018). Whereas Isl1 is expressed in a ring-like domain in reptiles and fish (Tessadori et al 2012;Jensen et al 2017b), it is confined to a small subset of the sinuatrial junction in adult mammals and birds, which, Figure 2.…”

Nkx2-5 defines distinct scaffold and recruitment phases during formation of the cardiac Purkinje fiber network

“…PFs are organized in a complex network of fascicles forming ellipsoidal structures 3 . Despite their functional importance and identification of PFs as a major trigger of ventricular arrhythmias 4 , it is still unclear how the complex PF network forms during ventricular morphogenesis [5][6][7][8] .…”