Mechanisms of cell transformation in the embryonic heart

The process of cell transformation in the heart is a complex one. By use of the invasion bioassay, we have been able to identify several critical components of the cell transformation process in the heart. TGF beta 3 can be visualized as a switch in the environment that contributes to the initial process of cell transformation. Our data show that it is a critical switch in the transformation process. Even so, it is apparently only one of the factors involved. Others may include other TGF beta family members, the ES antigens described by Markwald and co-workers and additional unknown substances. Observing the sensitivity of the process to pertussis toxin, there is likely to be a G-protein-linked receptor involved, yet we have not identified a known ligand for this type of receptor. Clearly, there are several different signal transduction processes involved. The existence of multiple pathways is consistent with the idea that the target endothelial cells receive a variety of environmental imputs, the sum of which will produce cell transformation at the correct time and place. Adjacent endothelial cells of the ventricle that do not undergo cell transformation are apparently refractory to one or more of the stimuli. Figure 4 depicts a summary diagram of this invasion process with localization of most of the molecules mentioned in this narrative. As hypothesized here, elements of the transformation process may recapitulate aspects of gastrulation. Since some conservation of mechanism is expected in cells, it is not surprising that cells undergoing phenotypic change might reutilize mechanisms used previously to produce mesenchyme from the blastodisk. Though we have preliminary data to suggest this point, confirmation of the hypothesis by perturbation of genes such as brachyury, msx-1, etc. will be required to establish this point. The advantage of this hypothesis is that it provides, from the work of others in the area of gastrulation, a ready source of molecules and mechanisms that can be tested in the transforming heart. Whereas, perturbation of such mechanisms at gastrulation may be lethal to the embryo, such molecules and mechanisms may be responsible for the high incidence of birth defects in the heart.