Follistatin-like 1 in development and disease

Follistatin-like 1 (Fstl1) is a secreted glycoprotein which is highly expressed during development and disease , including cardiac disease and cancer. In the early mouse embryo Fstl1 is broadly expressed but with ongoing development, its expression pattern becomes restricted to mesenchymal cells. A detailed analysis of the available commercial antisera directed against Fstl1 was performed, allowing the detailed analysis of the expression pattern of Fstl1 during mouse cardiac development and disease. After a myocardial infarction (MI), Fstl1 is highly and transiently expressed in the damaged area, especially in activated and proliferative fibroblasts involved in the scar formation. Deletion of Fstl1 from proliferating fibroblasts in the forming scar, results in cardiac rupture within one week after surgery due to impaired scar formation. Studying the transcriptional regulation of Fstl1 expression, two hypoxia responsive elements were identified, of which one was shown to be TGF-β responsive. Testing these regulatory elements in vivo showed that these sequences drive the transient expression of the reporter in the infarct area after the induction of an MI, which closely resembles the endogenous Fstl1 expression.
In an attempt to discover pathogenic mutations in the Fstl1 gene, over 50 patients with cardiac and skeletal defects resembling the Fstl1 knock-out phenotype were screened. Two novel variants were identified in regions that might regulate gene expression.
Taking together, our data shows the cardioprotective role of Fstl1 during myocardial infarction and provides new insights for developing novel therapies.