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Early heart morphogenesis: cellular and molecular perspectives

Cardiomyocyte specification occurs during gastrulation and involves canonical Wnt signaling to define the heart fields. Acute exposure of the embryo during gastrulation to either the drug lithium (Li) or to homocysteine (HCy) in the folic acid cycle, gives rise to similar heart defects. Li mimics Wnt/beta‐catenin signaling by inactivating glycogen synthase kinase‐3. Li use during pregnancy is associated with Ebstein's Anomaly. We determined by echocardiography, that exposure of mouse embryos by an i.p. injection of Li/HCy on embryonic day E6.75 induces cardiac and valve defects. A single dose of Li (25 mM) or of HCy (75 µM) on E5.5‐6.5 results in mouse embryonic lethality; on E6.75‐7.0, both induce tricuspid and semilunar valve defects. The tricuspid valve septal leaflet fails to delaminate, a characteristic of Ebstein's Anomaly. During chick cardiac specification, Li, Wnt 3A, or HCy similarly affect chick cardiogenesis with severity of anomalies based on timing of exposure. The secreted Wnt antagonist Dickkopf‐1 acts extracellularly to repress Wnt signaling resulting in the upregulation of Hex, an inducer of cardiomyogenesis. Exposure of stages 3+/4 chick embryos to Li/Wnt3A/ HCys inhibits Hex and Islet‐1 gene expression in the cardiogenic crescent. Taken together, these results suggest Li and HCy effects on cardiac development intersect via an augmention of inhibitory Wnt/beta‐catenin signaling. Support: NHLBI; AHA