TGFbeta Type III and TGFbeta Type II receptors have distinct activities during epithelial-mesenchymal cell transformation in the embryonic heart

Abstract

During the early stages of heart development, progenitors for the heart valves and septa come from endothelial cells via a developmental process known as "epithelial-mesenchymal cell transformation." This process is restricted to the atrioventricular (AV) canal and outflow tract portions of the embryonic heart. TGFbeta signal transduction pathways play critical roles during epithelial-mesenchymal cell transformation in heart development. Previously, we showed that both TGFbeta Type II (TbetaRII) and Type III (TbetaRIII) receptors are required to mediate epithelial mesenchymal cell transformation in chick heart. Further, distinct TGFbeta2 and TGFbeta3 activities correspond to separate components of the embryonic cell transformation process. Studies by others of TGFbeta-mediated inhibition of cell proliferation produced a model where TbetaRIII functions by facilitating TGFbeta2 binding to TbetaRII. In the present study, we provide evidence that TbetaRIII mediates distinct cellular responses from those of TbetaRII. Blocking antibody for TbetaRIII, but not antibody against TbetaRII, specifically inhibits the endothelial cell-cell separation step. Examination of developmental markers, perturbed by blocking TbetaRIII antibody, revealed a pattern of expression distinctively different from that of TbetaRII antibody treatment. These data show that a distinct TbetaRIII-mediated process is required for endothelial cell-cell separation during epithelial mesenchymal cell transformation. As TGFbeta2 mediates endothelial cell-cell separation, the data point to a specific association of TGFbeta2 and TbetaRIII in the cell separation step of epithelial mesenchymal cell transformation. We conclude that distinct TbetaRII and TbetaRIII signal transduction pathways mediate epithelial-mesenchymal cell transformation in the heart.