Akademik Veri Yönetim Sistemi
MANIPAL GENETICS UPDATE VII Cellular and Animal Models for Rare Genetic Diseases, Udupi, Hindistan, 18 - 20 Ocak 2024, (Yayınlanmadı)
Mutagenesis in inbred mice followed by Whole Exome Sequencing (WES) is an effective approach to recover mutations causing heritable diseases. This method allowed us to identify Adamts6, a disintegrin metalloprotease with thrombospondin motifs-6, as a gene that can cause syndromic congenital heart defects (CHD). Adamts6 mutant pups exhibited double outlet right ventricle and atrioventricular septal defect, CHD likely arising from disturbance of the extracellular matrix (ECM) in the cardiac cushions. As ECM in the cardiac cushions regulates endothelial-mesenchymal transition and mesenchymal cell migration, we investigated in the mouse embryonic fibroblasts (MEFs), focal adhesions (FA), key structure mediating cell adhesion to the ECM, In mutant MEFs, FA length was significantly reduced, and did not change with administration of TGF-β, key regulator of mesenchymal cell migration in the cardiac cushions. We examined migration of the MEFs cultured in 3D-collagen matrix to better simulate environment of the cardiac cushions. This showed an increase in migration rate in mutant MEFs. In vivo relevance of these MEF findings was demonstrated with analysis of atrioventricular cushions explanted on the 3D-collagen matrix, which also showed elevated migration in the mutant explants. Together these observations suggest CHD in the Adamts6 mutant may arise from cardiac cushions defects due to reduction in focal adhesion contacts causing increase in cell invasion into the cardiac cushions. The role of ADAMTS6 in human CHDs will need to be investigated in the future.