By Dean Haycock

Special To BioWorld Today

When cast members of the musical Damn Yankees sing, ¿You gotta have heart, miles and miles of heart,¿ they certainly are not thinking about embryology. Their admonition nevertheless is particularly relevant to that discipline.

¿The heart, while it is forming, also has to function,¿ said H. Scott Baldwin, co-director of cardiovascular research at the Children¿s Hospital of Philadelphia. ¿I think that escapes many people who aren¿t in the heart field. You can be born without a brain, without limbs, without a kidney; you can almost be born without a liver, you can be born without lungs. But you can¿t be born without a heart.¿

In the mouse, the heart starts to beat and circulate fluid after only eight and one-half days, according to Baldwin. Even at this early stage of development, the circulation is unidirectional, due to the presence of swellings that act like ¿ and will eventually develop into ¿ true valves. These swellings are called endocardial cushions. When they fail to develop properly, the result is congenital heart disease, which affects about one in 100 children.

¿It is an epidemic, the most frequent form of birth defect there is,¿ Baldwin said. ¿Of the one in 100, probably anywhere from 60 percent to 80 percent involve some defect in valve formation. So, the process itself is absolutely critical. We know very little about it,¿ Baldwin said.

A paper in today¿s issue of Science, ¿Requirement of Type III TGF-beta Receptor for Endocardial Cell Transformation in the Heart,¿ tells us a lot more about it. The report helps explain how the cells in these cushions are directed to form the valves and dividing walls in the mature heart while nearby cells are not. Author Joey Barnett and his colleagues show that the Type III TGF-beta receptor plays a key role in the process.

New Focus On How Signals Are Interpreted

¿The paper supplies for us a candidate gene for atrioventricular cushion defects in kids,¿ said Barnett, assistant professor of medicine and pharmacology and a member of the division of cardiovascular medicine at Vanderbilt University Medical Center, in Nashville.

The finding not only answers an important question in the field of cardiac development, but spotlights a growth factor receptor that, until now, had not appeared as interesting as others in its family.

While a complex of the Type I and Type II TGF-beta receptors were known to mediate the effects of TGF-beta on growing and differentiating cells, the Type III TGF-beta receptor has been regarded as a mere facilitator of the other receptors. It was not thought capable of directly signaling a cell. The identification of its role as a trigger in the development of heart valves gives the Type III receptor a new, higher status ¿ one that should prompt new research into the actions of TGF-beta.

Baldwin said the paper ¿identifies a receptor that is clearly involved in interpreting that signal. That is why I think it is so important, because we¿ve focused [in the past] on the signals but we haven¿t focused on how those signals are received and interpreted.¿

The researchers generated polyclonal antisera to a part of the TGF III receptor that sticks out from cells. They used these antibodies to label the receptor, and show it is located on cardiac endothelial cells that transform, and eventually form heart valves. Studying chick cells in vitro, Barnett et al. also demonstrated that TGF III receptor-specific antisera inhibits changes in these cells and the migration that accompanies differentiation.

In other words, when they blocked the receptor, they blocked the transformation that leads to valve formation.

¿That, in itself, is interesting, but [the research] wouldn¿t have made it into Science just with that,¿ Baldwin said. ¿It would have been a descriptive paper.¿ But, he added, researchers were able to show that, when they introduced the gene for the TGF III receptor into ventricular endothelial cells ¿ which don¿t normally have the potential to transform ¿ these cells express the TGF III receptor, and become capable of transforming in response to TGF-beta. The work strongly suggests that the receptor is responsible for localizing transformation in the heart. It also indicates a key role for the receptor in TGF-beta signaling.

Search For Downstream¿ Receptor

Barnett said transforming growth factor beta ¿has been implicated in a number of other normal and pathological processes in the body, from atherosclerosis to tumor progression, for example. We know a lot about TFG-beta signal transduction, especially as it relates to the Type II and the Type I TGF-beta receptor. Mutations in those receptors occur in certain human tumors. TGF-beta is a very pleiotropic (i.e., its gene controls a variety of seemingly unrelated biological effects), and it has been difficult to understand many of the activities or changes that we see in cells or tissues in response to TGF-beta.

¿I think our demonstration that we see a specific biology that can be attributed to, and requires, the Type III receptor tells us that we need to look carefully at the Type III receptor to see whether it might be tapping into an as yet undescribed signal transduction pathway,¿ he added. ¿If so, that means that the Type III receptor could be a target for manipulation of this system, independent of the Type I and Type II.¿

Barnett and his colleagues want to identify the molecule that is ¿downstream¿ from the Type III receptor. ¿If the Type III receptor is transmitting a unique signal into the cell, how does it do that?¿ Barnett asked. ¿Does it tie into some existing cellular machinery that we already know something about, or does it do it through an as yet undescribed pathway?¿

The work could eventually lead to progress in a field that, until now, has been disappointing: the generation of artificial valves. ¿We haven¿t yet said, OK, let¿s put an endothelial cell on there that is either capable of forming a valve or maintaining a valve,¿¿ Baldwin said. ¿There are implications down the road for valve morphogenesis, repair of injured or infected valves and gene therapy.¿

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