Dual developmental role of transcriptional regulator Ets1 in Xenopus cardiac neural crest versus heart mesoderm

Aims: Ets1 is an important transcription factor that is expressed in both the cardiac neural crest and heart mesoderm of vertebrate embryos. Moreover, Ets1 deletion in humans results in congenital heart abnormalities. To clarify the functional contributions of Ets1 in cardiac neural crest versus heart mesoderm, we performed tissue-targeted loss of function analysis to compare the relative roles of Ets1 in these two tissues during heart formation using Xenopus embryos as a model system. Methods and Results: We confirmed by in situ hybridization analysis that Ets1 is expressed in neural crest and heart mesoderm during embryogenesis. Using a translation-blocking antisense morpholino to knockdown Ets1 protein selectively in the neural crest, we observed defects in neural crest delamination from the neural tube, collective cell migration, as well as segregation of neural crest streams in the cranial and cardiac regions. Many cardiac neural crest cells failed to reach their destination in the heart, resulting in defective aortic arch artery formation. A different set of defects was noted when Ets1 knockdown was targeted to heart mesoderm. The formation of the primitive heart tube was dramatically delayed and the endocardial tissue appeared depleted. As a result, the conformation of the heart was severely disrupted. In addition, the outflow tract septum was missing, and trabeculae formation in the ventricle was abolished. Conclusion: Our study shows that Ets1 is required in both the cardiac neural crest and heart mesoderm, albeit for different aspects of heart formation. Our results reinforce the suggestion that proper interaction between these tissues is critical for normal heart development.