The role of RNA binding proteins in heart development and congenital heart defects

ABSTRACT Hypoplastic left heart syndrome (HLHS) is a congenital heart disease with a high mortality rate. Infants with this syndrome are born with circulation problems due to hypoplasia of the left part of the heart that includes aorta, left ventricle, mitral valve and aortic valve. Infants may need to undergo a series of open-heart surgeries to restore systemic circulation. Even after the surgeries, these patients can develop heart failure and other complications due to the overload on the right ventricle that serves as the single ventricle. Very little is known about the etiology and pathogenic mechanisms of HLHS. Recent human genetic studies identified de novo loss of function mutations in the RNA binding protein RBFOX2 that are linked to the HLHS phenotype. It is currently unknown how RBFOX2 contributes to HLHS developmental defects. This is mainly because of our lack of knowledge regarding the role of RBFOX2 in cardiovascular development and its target RNAs in the embryonic heart. Using our Rbfox2 conditional knockout mouse model, which recapitulates several phenotypic, cellular, and molecular features of HLHS, we will address these urgent and clinically relevant questions utilizing genetic, molecular/cellular and state-of-the art custom designed sequencing and computational approaches. Our main goal is to determine the mechanisms by which RBFOX2-regulated RNA networks contribute to cardiovascular development and investigate their contributions to HLHS. Our work will determine the underlying mechanisms of HLHS developmental defects caused by loss of RBFOX2. Ultimately, our findings will advance development of innovative HLHS therapeutic strategies by restoring aberrant RBFOX2-regulated gene expression in HLHS patients using modified antisense oligonucleotides in the future.