Abstract
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.
Highlights
Jun (a.k.a. c-Jun) is a highly conserved member of the multimeric activator protein 1 (AP-1) transcription factor complex [1]
Several cell populations are important for normal outflow tract (OFT) development and septation
To determine the specific cell populations in which Jun might be functioning to regulate cardiac morphogenesis, we examined the expression of Jun by in situ hybridization and immunohistochemistry at several stages of embryonic development between E8.5 and E15.5
Summary
Jun (a.k.a. c-Jun) is a highly conserved member of the multimeric activator protein 1 (AP-1) transcription factor complex [1]. Examination of the promiscuity of these dimer protein-protein interactions has revealed that as part of a DNAbinding complex, Jun is critical for multiple biological processes including cell proliferation, apoptosis, cell cycle progression and differentiation [6,7,8,9]. These cellular phenomena are critical for mammalian development and for diseases such as cancer, data regarding the role of Jun during embryogenesis is limited
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