Coronary vessel development is a highly coordinated process during heart formation. Abnormal development and dysfunction of the coronary network are contributory factors in the majority of heart disease. Understanding the molecular mechanisms that regulate coronary vessel formation is crucial for preventing and treating the disease. We report a zebrafish gene-trap vinculin b (vclb) mutant that displays abnormal coronary vessel development among multiple cardiac defects. The mutant shows overproliferation of epicardium-derived cells and disorganization of coronary vessels, and they eventually die off at juvenile stages. Mechanistically, Vclb deficiency results in the release of another cytoskeletal protein, paxillin, from the Vclb complex and the upregulation of ERK and FAK phosphorylation in epicardium and endocardium, causing disorganization of endothelial cells and pericytes during coronary vessel development. By contrast, cardiac muscle development is relatively normal, probably owing to redundancy with Vcla, a vinculin paralog that is expressed in the myocardium but not epicardium. Together, our results reveal a previously unappreciated function of vinculin in epicardium and endocardium and reinforce the notion that well-balanced FAK activity is essential for coronary vessel development.
The authors declare no competing or financial interests.
F.C., L.M., Q.W., X.G. performed experiments; F.C. , J.X. and J.Z. analyzed data; F.C. prepared figures; F.C., J.X. and J.Z. designed experiments and wrote the paper.
This work was financially supported through grants from the National Natural Science Foundation of China [31471359, 31590830]; the Ministry of Science and Technology of the People's Republic of China [2013CB945000]; and the Chinese Academy of Sciences [XDA01010108].
The complete cDNA sequence of Danio rerio vinculin b is available at GenBank under accession number KT862534.
Supplementary information available online at http://dev.biologists.org/lookup/doi/10.1242/dev.132936.supplemental
- Received November 12, 2015.
- Accepted July 26, 2016.