The Role of Activin Receptor-like Kinases and Nuclear Factor κB in Type III Transforming Growth Factor β Receptor Signaling

Abstract

Congenital heart disease (CHD) is the most common type of birth defect affecting eight out of every 1,000 newborns, causing more deaths in the first year of life than any other birth defect. A significant fraction of CHD is associated with abnormal valve structure and function. A detailed understanding of the early signaling events that regulate and guide cardiac valve formation is required to identify new therapeutic targets. Here, I focus on the role of Type III Transforming Growth Factor β Receptor (TGFβR3) in Endocardial epithelial to mesenchymal transformation (EMT), a critical step in valvular development. Using an in vitro assay of endocardial EMT I used small molecule inhibitors to establish that ALK2 and ALK3 are both required for endocardial EMT. Specifically, I demonstrated that ALK2 and ALK3 are downstream of TGFβR3. Finally, I used small molecule inhibitors of the NF-κB pathway to implicate this signaling system in endocardial EMT. These studies identify and clarify the role of specific pathways endocardial EMT which furthers our understanding of TGFβR3 signaling and early valve formation.