title: Pocket proteins critically regulate cell cycle exit of the trabecular myocardium and the ventricular conduction system.
abstract: During 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.
authors.affiliation: Leon H. Charney Division of Cardiology, New York University School of Medicine , New York, NY 10016 , USA ; Heart Rhythm Center, New York University School of Medicine , New York, NY 10016 , USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Park
authors.forename: Rose O
authors.initials: RO
authors.lastname: Tompkins
authors.forename: Fangyu
authors.initials: F
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Colin K L
authors.initials: CK
authors.lastname: Phoon
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
authors.forename: Glenn I
authors.initials: GI
authors.lastname: Fishman
keywords: Cardiac conduction system; Cardiogenesis; Cell cycle; Chamber development; Pocket proteins; Trabecular myocardium