Mentor(s): Jennifer Schumacher, Ph.D., and Benjamin Akande

Vertebrate heart formation depends on coordinated signaling among the first heart field, the second heart field (SHF), and neural crest cells (NCC). The cardiac outflow tract (OFT) and the adjacent bulboventricular (BV) valve are formed by both SHF and NCC lineages. Approximately 30% of human congenital heart malformations affect these and other OFT structures. Though this subject has been extensively studied, the cellular and molecular basis of OFT development remains poorly understood. Here, we report a novel zebrafish mutant, pendulum (pen), which enables us to explore these mechanisms. In pen mutants, we observe endocardial expansion and reduced smooth muscle cells in the OFT, indicating a defective SHF contribution. Transcriptome profiling indicates TGF-β signaling upregulation, which is crucial in SHF and NCC lineage. Extending our analysis to NCC derivatives, we employed two-color acid-free cartilage and bone staining at 4 days post fertilization (4 dpf) and observed disrupted craniofacial cartilage organization, which points towards defective NCC migration and differentiation. These findings establish pen as a model of value for studying SHF–NCC interaction and provide a system for research into therapeutic strategies against OFT malformations. 

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