Our long-term goal is to understand the molecular mechanisms by which disease genes disrupt normal cardiovascular development and function. Cardiovascular malformations and cardiomyopathy are major causes of morbidity and mortality world-wide and are particularly common among the 1:5000 newborns that have terminal or interstitial deletions of chromosome 1p36. The dosage-sensitive genes on chromosome 1p36 that contribute to these cardiac-related problems have yet to be fully elucidated. The arginine-glutamic acid dipeptide (RE) repeats gene (RERE) is located in a critical region of 1p36 associated with the development of cardiovascular malformations and cardiomyopathy. RERE is a cardiac-expressed nuclear receptor coregulator which positively regulates retinoic acid signaling through its interaction with NR2F2. We have shown that RERE-deficient embryos have aortic arch anomalies, double outlet right ventricle, transposition of the great arteries and perimembranous ventricular septal defects on a C57BL/6 background. We subsequently demonstrated that Rere interacts genetically with Gata4-a retinoic acid-responsive transcription factor encoding gene-during valvular, septal, aortic arch and outflow tract development. In our first specific aim, we will determine if Rere and Gata4 interact genetically in the endocardium to affect the development of the atrioventricular (AV) valvuloseptal complex. This will be accomplished by analyzing the progeny of mice in which Rere and Gata4 have been targeted in the endocardium using a transgenic Tie2-Cre. We will also ablate Rere in the endocardium using the same transgenic Tie2-Cre to determine if expression of RERE in these cells is required for normal AV valvuloseptal development. These experiments are particularly important since valvular and septal anomalies are the most common cardiovascular malformations caused by 1p36 deletions and mutations in GATA4. On a BL6/129S6 background, RERE-deficient mice do not have cardiovascular malformations but spontaneously develop cardiac fibrosis and cardiac hypertrophy. This is consistent with RERE's role as a positive regulator of retinoic acid signaling, which suppresses cardiac fibrosis and myocardial hypertrophy through its actions in cardiomyocytes. However, we cannot eliminate the potential impact of systemic RERE deficiency in the development of these defects using traditional knockout models. To overcome this problem, we generated cardiomyocyte-specific Rere-knockout mice on a mixed background using a transgenic Myh6- Cre. In our second specific aim, we will use these mice to determine RERE's cell-autonomous effects on baseline cardiac function and the heart's response to pressure overload. These studies will lay the foundation from which novel preventative and therapeutic strategies can be developed and tested to help individuals affected by cardiovascular malformations and cardiomyopathy. These studies will also generate mouse models in which clinical interventions can be tested.
RERE and other genes on chromosome 1p36 are deleted in some individuals with heart defects and cardiomyopathy. In these studies we will use mouse models to learn more about how deletion of RERE contributes to these life-threatening heart problems. This knowledge will help physicians care for individuals with 1p36 deletions and may lead to the development of new ways of treating and preventing heart defects and cardiomyopathy.