Coronary development is regulated by ATP-dependent SWI/SNF chromatin remodeling component BAF180.
Dissecting the molecular mechanisms that guide the proper development of epicardial cell lineages is critical for understanding the etiology of both congenital and adult forms of human cardiovascular disease. In this study, we describe the function of BAF180, a polybromo protein in ATP-dependent SWI/SNF chromatin remodeling complexes, in coronary development. Ablation of BAF180 leads to impaired epithelial-to-mesenchymal-transition (EMT) and arrested maturation of epicardium around E11.5. Three-dimensional collagen gel assays revealed that the BAF180 mutant epicardial cells indeed possess significantly compromised migrating and EMT potentials. Consequently, the mutant hearts form abnormal surface nodules and fail to develop the fine and continuous plexus of coronary vessels that cover the entire ventricle around E14. PECAM and *-SMA staining assays indicate that these nodules are defective structures resulting from the failure of endothelial and smooth muscle cells within them to form coronary vessels. PECAM staining also reveal that there are very few coronary vessels inside the myocardium of mutant hearts. Consistent with this, quantitative RT-PCR analysis indicate that the expression of genes involved in FGF, TGF, and VEGF pathways essential for coronary development are down-regulated in mutant hearts. Together, these data reveal for the first time that BAF180 is critical for coronary vessel formation.
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Richard Simches Research Center, 185 Cambridge Street, Boston, MA 02114, USA.
Xuling
X
Huang
Xiaolin
X
Gao
Ramon
R
Diaz-Trelles
Pilar
P
Ruiz-Lozano
Zhong
Z
Wang
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003331:Coronary Vessels / Q000196:embryology* / Q000502:physiology; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian / Q000502:physiology; D005318:Fetal Heart / Q000502:physiology*; D024002:HMGB Proteins; D006321:Heart / Q000254:growth & development*; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010496:Pericardium / Q000196:embryology / Q000502:physiology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; D024002:HMGB Proteins; D009687:Nuclear Proteins; C496872:Pbrm1 protein, mouse; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D014157:Transcription Factors; D000255:Adenosine Triphosphate