Mentor: Jennifer Schumacher, Ph.D.

Congenital heart defects (CHD) occur in 1 in every 100 babies born daily in the United States of America. Although CHD can be surgically repaired, it has been shown to complicate heart health with arrhythmia, heart attack, and eventually death. The cardiac outflow tract (OFT), which gives rise to the aorta and pulmonary trunk, is one of the many heart vessels that is highly compromised. OFT malformations account for  ~⅓ of all daily CHD cases. The molecular basis of OFT formation remains a gap in the literature that needs to be understood. Particularly, the cellular and molecular drivers that govern OFT formation. To study in-depth the OFT formation, we chose zebrafish as a model due to its fecundity, rapid development, and transparent skin, making it amenable to cardiovascular assessment. Here, we analyze a novel zebrafish mutant called pendulum (pen) that displays extensive heart deformities, including pericardial edema, blood pooling in heart, diminished ventral aorta, malformed aortic valve, and absent/reduced OFT smooth muscle. Because pen mutants were generated via ethylnitrosourea, we aim to identify the genetic lesion contributing to the phenotype. Preliminary single-nucleotide polymorphism analysis using the in-silico MMAPPR2 pipeline on 72 hpf bulk RNA-Seq pen embryos reveals a nonsense-mediated decay in wipf3 (WAS/WASL interacting protein family member 3), an actin cytoskeletal regulator that evades immune response to disrupt aortic smooth muscle destruction. To determine the possible interaction between wipf3 and the pen phenocopy, we aim to characterize the wipf3 gene. This involves a detailed analysis of gene sequence, expression levels, and location via in-situ hybridization, and the impact of wipf3 mRNA overexpression in pen. Understanding the molecular contributions of wipf3 to the pen phenotype will provide novel insights into cytoskeleton dynamics and OFT development, fostering a better understanding of CHD etiologies.

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