The role of Follistatin-like 1 (Fstl1) in the developing heart

Congenital heart defects (CHD) are one of the most common type of birth defects affecting approximately 0.8% of live born infants. However, in as little as 15% of the cases of CHD an underlying genetic etiology has not been identified. Previous studies have suggested a role of Follistatin-like 1 (Fstl1) in congenital cardiac malformations and cardiovascular disease. Fstl1 is a secreted protein that is initially ubiquitously expressed during early heart development and then becomes gradually restricted to the non-myocardial component of the heart. In this thesis, we focus on trying to understand the function and the role of Fstl1 during heart development and disease. Genetic deletion of Fstl1 results in death of homozygous knock out mice at birth due to respiratory distress. These Fstl1 knock out mice show an array of abnormalities including cardiac, lung and skeletal defects. In the heart, loss of Fstl1 results in an increase in myocardial volume and prenatal transition from hyperplastic to hypertrophic growth. Based on a genome-wide phosphoproteome analysis, we uncovered a novel signaling pathway activated by Fstl1 involving RhoGTPase and the Gpr124 receptor. Ablation of Fstl1 from the endocardial/endothelial lineage revealed that Fstl1 is crucial in valve development and results in incompetent myxomatous mitral valves, which ensues in diastolic dysfunction, heart failure with preserved ejection fraction and eventually death. Screening unresolved patients with CHD that resemble the mouse phenotype identified genetic variants but failed to identify mutations in the protein-coding region of Fstl1.