Adriana C Gittenberger-de Groot1,2, Tamara Hoppenbrouwers3, Lucile Miquerol4, Yasuhiro Kosaka5, Robert E Poelmann6, Lambertus J Wisse3, H Joseph Yost7, Monique R M Jongbloed8,3, Marco C Deruiter3, Luca Brunelli9. 1. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands. acgitten@lumc.nl. 2. Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands. acgitten@lumc.nl. 3. Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands. 4. Aix-Marseille University, CNRS IBDM, Marseille, France. 5. Department of Pediatrics (Neonatology), University of Utah School of Medicine, Salt Lake City, Utah. 6. Biology Institute, Leiden University, Leiden, The Netherlands. 7. Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah. 8. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands. 9. Department of Pediatrics (Neonatology), University of Utah School of Medicine, Salt Lake City, Utah. luca.brunelli@genetics.utah.edu.
Abstract
BACKGROUND: 14-3-3ε plays an important role in the maturation of the compact ventricular myocardium by modulating the cardiomyocyte cell cycle via p27kip1 . However, additional cardiac defects are possible given the ubiquitous expression pattern of this protein. RESULTS: Germ line deletion of 14-3-3ε led to malalignment of both the outflow tract (OFT) and atrioventricular (AV) cushions, with resulting tricuspid stenosis and atresia, mitral valve abnormalities, and perimembranous ventricular septal defects (VSDs). We confirmed myocardial non-compaction and detected a spongy septum with muscular VSDs and blebbing of the epicardium. These defects were associated with abnormal patterning of p27kip1 expression in the subendocardial and possibly the epicardial cell populations. In addition to abnormal pharyngeal arch artery patterning, we found deep endocardial recesses and paucity of intramyocardial coronary vasculature as a result of defective coronary plexus remodeling. CONCLUSIONS: The malalignment of both endocardial cushions provides a new explanation for tricuspid and mitral valve defects, while myocardial non-compaction provides the basis for the abnormal coronary vasculature patterning. These abnormalities might arise from p27kip1 dysregulation and a resulting defect in epithelial-to-mesenchymal transformation. These data suggest that 14-3-3ε, in addition to left ventricular non-compaction (LVNC), might be linked to different forms of congenital heart disease (CHD). Developmental Dynamics 245:1107-1123, 2016.
BACKGROUND: 14-3-3ε plays an important role in the maturation of the compact ventricular myocardium by modulating the cardiomyocyte cell cycle via p27kip1 . However, additional cardiac defects are possible given the ubiquitous expression pattern of this protein. RESULTS: Germ line deletion of 14-3-3ε led to malalignment of both the outflow tract (OFT) and atrioventricular (AV) cushions, with resulting tricuspid stenosis and atresia, mitral valve abnormalities, and perimembranous ventricular septal defects (VSDs). We confirmed myocardial non-compaction and detected a spongy septum with muscular VSDs and blebbing of the epicardium. These defects were associated with abnormal patterning of p27kip1 expression in the subendocardial and possibly the epicardial cell populations. In addition to abnormal pharyngeal arch artery patterning, we found deep endocardial recesses and paucity of intramyocardial coronary vasculature as a result of defective coronary plexus remodeling. CONCLUSIONS: The malalignment of both endocardial cushions provides a new explanation for tricuspid and mitral valve defects, while myocardial non-compaction provides the basis for the abnormal coronary vasculature patterning. These abnormalities might arise from p27kip1 dysregulation and a resulting defect in epithelial-to-mesenchymal transformation. These data suggest that 14-3-3ε, in addition to left ventricular non-compaction (LVNC), might be linked to different forms of congenital heart disease (CHD). Developmental Dynamics 245:1107-1123, 2016.
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