Document Type
Article
Publication Date
9-19-2023
Identifier
DOI: 10.1161/JAHA.123.029683
Abstract
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. Crk and Crkl are ubiquitously expressed genes encoding cytoplasmic adaptors essential for cell signaling. This study aims to explore the specific role of Crk and Crkl in the endocardial lineage during heart valve development. Methods and Results We deleted Crk and Crkl 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 Crk and Crkl 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 Crk and Crkl. Loss of Crk and Crkl 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 Crk and Crkl 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.
Journal Title
J Am Heart Assoc
Volume
12
Issue
18
First Page
029683
Last Page
029683
MeSH Keywords
Apoptosis; Catheters; Cytosol; Endocardium; Signal Transduction; Animals; Mice; Heart Valves
Keywords
Crk; Crkl; endocardial cushion; endocardium; heart valve development.
Recommended Citation
Wu B, Wu B, Benkaci S, et al. Crk and Crkl Are Required in the Endocardial Lineage for Heart Valve Development. J Am Heart Assoc. 2023;12(18):e029683. doi:10.1161/JAHA.123.029683
- Usage
- Downloads: 18
- Abstract Views: 2
Comments
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made
Publisher's Link: https://doi.org/10.1161/jaha.123.029683