The SWI/SNF Complex Subunit BAF155 Is Essential For Normal Outflow Tract Septation And Regulates Mitochondrial Structure And Function During OFT Septation

Congenital heart disease(CHD)accounts to 5%defects in newborns,as a major medical problem in the world.It is significant to understand the mechanism of heart development,especially at early stages,in both scientific and clinical aspects.In the beginning of cardiogenesis,two populations of cardiac progenitors,called first heart field(FHF)and second heart field(SHF)from the lateral plate mesoderm migrate to the midline and form the primary heart tube.The tube undergoes looping resulting the heart to 3D structure.Morphogenesis causes chamber separation and makes the primary heart tube to mature status.In these process,two cardiac progenitors show different contribution.Left ventricle is consisted of FHF lineage while the right ventricle,outflow tract,sinus venosus and the atrias come from the SHF lineage.The outflow tract is a transient tissue in heart development.In morphogenesis,this vessel is separated into aorta and pulmonary.Disruption in this process causes circulation disorder,such as persistent truncus arteriosus(PTA),double-outlet right ventricle(DORV),transposition of the great arteries(TGA),and overriding aorta(OA),which accounts one third of CHD.In particular,these diseases are lethal and severe.Neural crest cells,endothelial cells and SHF cells are considered involving OFT separation,but both cellular and molecular mechanism of OFT separation requires further investigation.BAF155,a core component of the SWI/SNF chromatin remodeling complex,is essential for early embryogenesis.Deficiency of BAF155 in mice leads to peri-implantation lethality.Gene expression profiling analysis suggested BAF155 participate into OFT development.To study the function of BAF155 in OFT development,Mef2c lineage specific ablation of BAF155 was performed and mutants died after birth showing defects in OFT and chamber separation.The results showed the essential role of BAF155 in these process.With genetic lineage tracing,we studied the cellular behavior of mutant cells in OFT development and observed excessive mesenchymal cells in mutant OFT cushions,which were derived from mutant Mef2C lineage.Protein quantification experiments further supported improved epithelial-mesenchymal transition in mutant OFT tissues.Based on these results,we suggested BAF155 regulated the balance of cell fate from SHF progenitors to mesenchymal cells.The disruption of this process may cause failure of OFT separation,finally leading to circulation disorder.On the other hand,mitochondrial structure and function were damaged in mutant SHF-derived cells.Mutant Mef2c-AHF+cells showed decreased mitochondrial number,defective structure and impaired functionTaken together,BAF155 in Mef2c-AHF+cells strictly controlled the proportion of Mef2c-AHF+cells contributing to the myocardium,endothelium and mesenchyme under normal metabolic environment during embryonic development.However,BAF155 ablation in the SHF and its descendants produced severe heart defects,despite the SWI/SNF complex seemed unaffected.Much more Mef2c-AHF+cells derived from the OFT wall contributed to the endocardial cushion and prevented OFT separating to pulmonary artery and aorta along with defective mitochondrial structure and function.