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Interrogating cardiovascular morphogenesis in zebrafish through small molecule perturbation


Congenital heart disease can originate with errors in embryonic cardiac morphogenesis. A critical step in heart formation is the migration of bilateral populations of cardiomyocytes to the midline where they fuse to initiate heart tube assembly. Although some genes have been shown to influence cardiac fusion, our understanding of this aspect of cardiac morphogenesis remains incomplete. The identification of small molecules that perturb cardiac fusion could provide further insight into the pathways regulating the early steps of heart formation. Through a small-scale screen of 276 compounds, we have identified two compounds, ketanserin and scopoletin, that disrupt early cardiac morphogenesis. Treatment of embryos with ketanserin results in an increase in the circumference of the myocardial ring at the completion of cardiac fusion, accompanied by defects in the sheet of endocardial cells that will later line the heart tube. Ketanserin treatment also results in blood regurgitation at the atrioventricular (AV) valve and ectopic expression of atrioventricular canal (AVC) markers in the ventricle. Embryos treated with scopoletin exhibit a dysmorphic myocardial ring and defects in endocardial sheet integrity. In addition, FACS analysis revealed that scopoletin treatment leads to an increased number of erythrocytes in the early embryo. This work demonstrates the utility of small molecule screening for the identification of novel modulators of cardiac fusion and for the elucidation of potential connections between the regulation of cardiac fusion and cardiovascular processes. Future studies will illuminate further details about the precise molecular mechanisms by which ketanserin and scopoletin can influence cardiovascular development

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