Jun is required in Isl1-expressing progenitor cells for cardiovascular development

• Published in: PloS one Vol. 8; no. 2; p. e57032
• Main Authors: Zhang, Tao, Liu, Junchen, Zhang, Jue, Thekkethottiyil, Eldhose B, Macatee, Timothy L, Ismat, Fraz A, Wang, Fen, Stoller, Jason Z
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.02.2013; Public Library of Science (PLoS)
• Subjects: Activator protein 1; Animals; Aorta; Aortic arch; Apoptosis; Biology; Cancer; Cardiovascular System - embryology; Cardiovascular System - metabolism; Cell cycle; Cell death; Cell survival; Cells (biology); Clonal deletion; Congenital heart defects; Coronary artery disease; Cushions; Defects; Embryogenesis; Embryonic development; Embryonic Development - genetics; Embryonic growth stage; Embryos; Endocardium - embryology; Endocardium - metabolism; Endoderm; Endothelial cells; Endothelium; Fetuses; Gene Expression Regulation, Developmental; Gene Knockout Techniques; Genetic disorders; Genotype; Gestation; Heart; Heart Defects, Congenital - embryology; Heart Defects, Congenital - genetics; Heart diseases; Heart Valves - embryology; Heart Valves - metabolism; Hospitals; Hybridization; Hyperplasia; LIM-Homeodomain Proteins - genetics; LIM-Homeodomain Proteins - metabolism; Medicine; Mice; Mice, Knockout; Morphogenesis; Muscles; Mutation; Myocardium; Neural crest; Neural stem cells; Pathogenesis; Pattern formation; Patterning; Pediatrics; Pharynx; Pregnancy; Proteins; Proto-Oncogene Proteins c-jun - genetics; Proto-Oncogene Proteins c-jun - metabolism; Pulmonary arteries; Receptor, TIE-2 - genetics; Receptor, TIE-2 - metabolism; Rodents; Smooth muscle; Stem cells; Stem Cells - metabolism; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Veins & arteries; Ventricle; Ventricular Septum - enzymology; Ventricular Septum - metabolism; United States > US; Texas; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0057032

Jun is a highly conserved member of the multimeric activator protein 1 transcription factor complex and plays an important role in human cancer where it is known to be critical for proliferation, cell cycle regulation, differentiation, and cell death. All of these biological functions are also crucial for embryonic development. Although all Jun null mouse embryos die at mid-gestation with persistent truncus arteriosus, a severe cardiac outflow tract defect also seen in human congenital heart disease, the developmental mechanisms are poorly understood. Here we show that murine Jun is expressed in a restricted pattern in several cell populations important for cardiovascular development, including the second heart field, pharyngeal endoderm, outflow tract and atrioventricular endocardial cushions and post-migratory neural crest derivatives. Several genes, including Isl1, molecularly mark the second heart field. Isl1 lineages include myocardium, smooth muscle, neural crest, endocardium, and endothelium. We demonstrate that conditional knockout mouse embryos lacking Jun in Isl1-expressing progenitors display ventricular septal defects, double outlet right ventricle, semilunar valve hyperplasia and aortic arch artery patterning defects. In contrast, we show that conditional deletion of Jun in Tie2-expressing endothelial and endocardial precursors does not result in aortic arch artery patterning defects or embryonic death, but does result in ventricular septal defects and a low incidence of semilunar valve defects, atrioventricular valve defects and double outlet right ventricle. Our results demonstrate that Jun is required in Isl1-expressing progenitors and, to a lesser extent, in endothelial cells and endothelial-derived endocardium for cardiovascular development but is dispensable in both cell types for embryonic survival. These data provide a cellular framework for understanding the role of Jun in the pathogenesis of congenital heart disease.