Vanderbilt University Medical Center scientists deciphered how the Type III TGF-beta receptor leads to the formation of valves and dividing walls in the heart, reports the March 26th issue of Science.
Their findings have particular relevance to the families of children with congenital heart defects, the leading cause of birth defect-related deaths. About 1 in 100 children born each year in the United States have heart defects, yet little is known about the causes, and surgery is often the only treatment option.
Joey V. Barnett, Ph.D., assistant professor of Medicine and Pharmacology and a member of the division of Cardiovascular Medicine, is interested in the role of growth factors in heart development, particularly how the valves and septa-dividing walls-of the heart are formed.
Their formation begins when the heart is only a simple tube and cells in a region called the atrioventricular (AV) cushion receive a signal that tells them to change shape, pull away from their neighbors and migrate. Those cells eventually multiply and give rise to the heart's valves and septa.
It has been a mystery why only a small population of cells receives the signal to change.
"Their neighbors never undergo this epithelial-mesenchymal transformation," Barnett said. "We wanted to know why, so we asked what cell surface receptors are found on the cells that transform but are missing on the cells that do not."
Transforming growth factor-beta (TGF-beta) has been suspected to play a role in transformation of the AV cushion cells, so Barnett and Christopher B. Brown, Ph.D. focused on the different types of TGF-beta receptors.
In the current report, they show that the Type III TGF-beta receptor is found on those cells in the developing heart that undergo the transformation.
"If we use experimental techniques in an in vitro assay to block this receptor on those cells, they don't transform," Barnett said. "Conversely, if we introduce this receptor into cells that normally would not respond-the neighbor cells, they do transform in response to TGF-beta."
The findings provide strong evidence that the Type III TGF-beta receptor is essential for AV cushion cell response and transformation.
Non-functional Type III TGF-beta receptor might cause some types of congenital heart defects. In fact, many affected children have defects in valves or septa that can be explained by failure of the AV cushion cells to transform and migrate.
Recently, these defects have been associated with damage to a region of chromosome 1 that includes the gene for the Type III TGF-beta receptor. Several groups are working hard to identify mutations in this receptor, Barnett said.
The Type III TGF-beta receptor has been something of a mystery. A complex of Type I and Type II TGF-beta receptors mediates the well-characterized effects of the growth factor TGF-beta on cell growth and differentiation. The Type III TGF-beta receptor is not capable of sending a signal into the cell by itself and was considered to be a facilitator of the Type I/II complex.
"The Type III receptor was the first TGF-beta receptor cloned, but we've been unable to assign a specific biological function for it," Barnett said. "It's remained an orphan in that regard."
The newly defined role for the Type III TGF-beta receptor in AV cushion transformation during heart development sparks questions about how this receptor sends signals.
"Our data suggest that the Type III TGF-beta receptor does more than facilitate transmission through the Type I/II receptor complex," Barnett said. "It looks like it must be using another signaling pathway that is independent of the other two receptor types."
The possibility of a new way for TGF-beta to send signals opens up a whole new area for research into this growth factor's actions.
These studies were supported by grants from the NIH, American Heart Association, and March of Dimes.
Materials provided by Vanderbilt University Medical Center. Note: Content may be edited for style and length.
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