Crk and Crkl Are Required in the Endocardial Lineage for Heart Valve Development

• Published in: Journal of the American Heart Association 2023-09, Vol.12 (18), p.e029683-e029683
• Main Authors: Wu, Bingruo, Wu, Brian, Benkaci, Sonia, Shi, Lijie, Lu, Pengfei, Park, Taeju, Morrow, Bernice E, Wang, Yidong, Zhou, Bin
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Catheters; Crk; Crkl; Cytosol; endocardial cushion; endocardium; Endocardium - embryology; heart valve development; Heart Valves - embryology; Mice; Original Research; Signal Transduction
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.123.029683

Background Endocardial cells are a major progenitor population that gives rise to heart valves through endocardial cushion formation by endocardial to mesenchymal transformation and the subsequent endocardial cushion remodeling. Genetic variants that affect these developmental processes can lead to congenital heart valve defects. and are ubiquitously expressed genes encoding cytoplasmic adaptors essential for cell signaling. This study aims to explore the specific role of and in the endocardial lineage during heart valve development. Methods and Results We deleted and specifically in the endocardial lineage. The resultant heart valve morphology was evaluated by histological analysis, and the underlying cellular and molecular mechanisms were investigated by immunostaining and quantitative reverse transcription polymerase chain reaction. We found that the targeted deletion of and impeded the remodeling of endocardial cushions at the atrioventricular canal into the atrioventricular valves. We showed that apoptosis was temporally increased in the remodeling atrioventricular endocardial cushions, and this developmentally upregulated apoptosis was repressed by deletion of and . Loss of and also resulted in altered extracellular matrix production and organization in the remodeling atrioventricular endocardial cushions. These morphogenic defects were associated with altered expression of genes in BMP (bone morphogenetic protein), connective tissue growth factor, and WNT signaling pathways, and reduced extracellular signal-regulated kinase signaling activities. Conclusions Our findings support that and have shared functions in the endocardial lineage that critically regulate atrioventricular valve development; together, they likely coordinate the morphogenic signals involved in the remodeling of the atrioventricular endocardial cushions.