Abstract
SummaryDuring development, the ventricular conduction system (VCS) arises from the trabecular or spongy myocardium. VCS and trabecular myocytes proliferate at a significantly slower rate than compact zone myocardial cells, establishing a transmural cell cycle gradient. The molecular determinants of VCS/trabecular myocyte cell cycle arrest are not known. Given the importance of pocket proteins (Rb, p107 and p130) in mediating G0/G1 arrest in many cell types, we examined the role of this gene family in regulating cell cycle exit of the trabecular myocardium and ventricular conduction system. Using a combinatorial knockout strategy, we found that graded loss of pocket proteins results in a spectrum of heart and lung defects. p107/p130 double knockout (dKO) hearts manifest dysregulated proliferation within the compact myocardium and trabecular bases, while the remaining trabecular region cell cycle exits normally. Consequently, dKO hearts exhibit defective cardiac compaction, septal hyperplasia and biventricular outflow tract obstruction, while the VCS appears relatively normal. Loss of all three pocket proteins (3KO) is necessary to completely disrupt the transmural cell cycle gradient. 3KO hearts exhibit massive overgrowth of the trabecular myocardium and ventricular conduction system, which leads to fetal heart failure and death. Hearts carrying a single pocket protein allele are able to maintain the transmural cell cycle gradient. These results demonstrate the exquisite sensitivity of trabecular and conduction myocytes to pocket protein function during ventricular chamber development.
Highlights
The ventricular conduction system (VCS), comprised of the His bundle, bundle branches, and the Purkinje fiber network, develops from the trabecular or spongy myocardium
Given the importance of pocket proteins (Rb, p107 and p130) in mediating G0/G1 arrest in many cell types, we examined the role of this gene family in regulating cell cycle exit of the trabecular myocardium and ventricular conduction system
Using a combinatorial knockout strategy, we found that graded loss of pocket proteins results in a spectrum of heart and lung defects. p107/p130 double knockout hearts manifest dysregulated proliferation within the compact myocardium and trabecular bases, while the remaining trabecular region cell cycle exits normally
Summary
The ventricular conduction system (VCS), comprised of the His bundle, bundle branches, and the Purkinje fiber network, develops from the trabecular or spongy myocardium. The proliferative capacity of VCS/trabecular myocytes is significantly attenuated while the compact myocardial zone proliferates at a significantly faster rate, creating a transmural cell cycle gradient (Mikawa et al, 1992a; Mikawa et al, 1992b; Soonpaa et al, 1996; Meilhac et al, 2003). Differential proliferation rates between the trabecular and compact myocardial zones are essential for proper chamber development. Specification of the VCS within the trabecular region allows for rapid impulse propagation throughout the spongy myocardium optimizing synchronized contraction of the ventricles. Indicative of their early cell cycle withdrawal, cells of the cardiac conduction system comprise less than 1% of the adult cardiomyocyte population. Significant advances have been made in unraveling the transcription factor pathways that regulate trabecular and conduction system development, very little is known about the cell cycle machinery governing this process (Shou et al, 1998; Chen et al, 2004; Pashmforoush et al, 2004; Grego-Bessa et al, 2007; Bakker et al, 2008)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
