Abstract
The endothelial-to-mesenchymal transition (EndMT) is a critical process that occurs during the development of the outflow tract (OFT). Malformations of the OFT can lead to the occurrence of conotruncal defect (CTD). SOX7 duplication has been reported in patients with congenital CTD, but its specific role in OFT development remains poorly understood. To decipher this, histological analysis showed that SRY-related HMG-box 7 (SOX7) was regionally expressed in the endocardial endothelial cells and in the mesenchymal cells of the OFT, where EndMT occurs. Experiments, using in vitro collagen gel culture system, revealed that SOX7 was a negative regulator of EndMT that inhibited endocardial cell (EC) migration and resulted in decreased number of mesenchymal cells. Forced expression of SOX7 in endothelial cells blocked further migration and improved the expression of the adhesion protein vascular endothelial (VE)-cadherin (VE-cadherin). Moreover, a VE-cadherin knockdown could partly reverse the SOX7-mediated repression of cell migration. Luciferase and electrophoretic mobility shift assay (EMSA) demonstrated that SOX7 up-regulated VE-cadherin by directly binding to the gene's promoter in endothelial cells. The coding exons and splicing regions of the SOX7 gene were also scanned in the 536 sporadic CTD patients and in 300 unaffected controls, which revealed four heterozygous SOX7 mutations. Luciferase assays revealed that two SOX7 variants weakened the transactivation of the VE-cadherin promoter. In conclusion, SOX7 inhibited EndMT during OFT development by directly up-regulating the endothelial-specific adhesion molecule VE-cadherin. SOX7 mutations can lead to impaired EndMT by regulating VE-cadherin, which may give rise to the molecular mechanisms associated with SOX7 in CTD pathogenesis.
Highlights
Congenital heart defect (CHD) is the most common form of human birth defects, affecting nearly 1 in 100 live births [1,2]
By quantitative real-time polymerase chain reaction (qRT-PCR) analysis, the expression of SM22α, FSP1 and CD44 were all significantly decreased in endocardial cell (EC) isolated from outflow tract (OFT) explants infected with AdV-SRY-related HMG-box 7 (SOX7) as compared to control samples, whereas vimentin and Notch3 (EndMT transcriptional factor) were unaffected (Supplementary Figure S3)
SOX7 has been associated with cardiovascular development, its functional roles during OFT development have not been fully elucidated, which was the goal of this study
Summary
Congenital heart defect (CHD) is the most common form of human birth defects, affecting nearly 1 in 100 live births [1,2]. Within the scope of CHD, conotruncal defect (CTD) including Tetralogy of Fallot (TOF), double outlet right ventricle (DORV), transposition of the great arteries (TGA), pulmonary atresia (PA), and persistent truncus arteriosus (PTA), account for 30% of human CHD, which causes significant morbidity and mortality [3]. The OFT is formed through interactions between multiple cardiac lineages, such as endocardial cells (ECs) and cardiomyocytes located within the heart itself, in addition to the migrating cells arising from the cardiac neural crest (CNC) [2]. A subpopulation of ECs undergo endothelial-to-mesenchymal transition (EndMT) and migrate into the cardiac jelly, and together, with the CNC cells, give rise to the OFT cushions [4–8]. Multiple critical genes and signaling pathways are involved in cardiac OFT development, including Tbx and Hand factors, with signaling occurring through the fibroblast growth factor, bone morphogenetic protein (BMP), and Notch [2,3]. Identifying CTD-causing genes and its underlying molecular mechanisms are required to gain a greater understanding of CTD development
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