Multiple Transforming Growth Factor-beta Isoforms and Receptors Function During Epithelial-mesenchymal Cell Transformation in the Embryonic Heart

Epithelial-mesenchymal cell transformation (EMT) is a critical process during development of the heart valves. Transition of endothelial cells into mesenchymal cells in the atrioventricular (AV) canal and the outflow tract regions of the heart form the cardiac cushions that eventually form the heart valves. Collagen gel invasion assay has aided in the identification of molecules that regulate EMT. Among those, transforming growth factor-beta (TGF-beta) ligands and receptors demonstrate a critical role during EMT. In the chick, TGF-beta ligands and some receptors have specific functions during EMT. TGF-beta2 mediates endothelial cell-cell activation and separation, and TGF-beta3 mediates cell invasion into the extracellular matrix. Receptors involved in the EMT process include TGF-beta receptor type II (TBRII), TBRIII, endoglin and the TBRI receptors, ALK2 and ALK5. In contrast, in the mouse model, TGF-beta2 is the only ligand involved in EMT. The TGF-beta2 null mouse has either increased EMT or a mesenchymal cell proliferation after EMT. However, functional studies of TGF-beta1 in vivo and in vitro showed that TGF-beta1 functions in the EMT of the mouse AV canal. Latent TGF-beta-binding protein (LTBP-1) and endoglin have a role in the EMT process. Therefore, TGF-betas mediate cardiac EMT in both embryonic species. Further studies will reveal the identification of ligand and receptor-specific activities.