The lub-dub of a healthy heart  pg. 6

Barnett and colleagues continue to tease apart the complexities of TGF-beta receptor signaling. They recently discovered that the type III TGF-beta receptor also has a role in the development of coronary blood vessels.

“It’s a recurring theme in developmental biology that nature uses the same, or similar, molecules over and over again in slightly different contexts,” Barnett says.

Bit of serendipity

Baldwin traces his research path back to a lecture at a Society for Pediatric Research meeting that he attended during his residency. At the meeting, Merton Bernfield, M.D., a Harvard neonatologist and pioneer on studies of the extracellular matrix who died in 2002, talked about how organs take shape.

“I was mesmerized,” Baldwin recalls. “I had already committed to a cardiology fellowship, and I remember sitting there thinking ‘I want to know how the extracellular matrix influences heart development.’”

During his fellowship research at the University of Iowa, Baldwin published the first paper demonstrating that a component of the extracellular matrix, hyaluronic acid, is important for heart development. And he became intrigued with the question of what patterns the heart – how the single tube loops and twists into an organ with chambers and valves. He suspected that the endocardial lining was involved in laying down the template for the heart.

At the time though – the late ’80s – it wasn’t possibly to identify endocardial cells, or even their endothelial cell precursors, in the embryo, Baldwin notes. Undeterred, he joined a lab at the Wistar Institute in Philadelphia, where over the next several years he cloned a mouse gene that identified endothelial cells.

Then came a bit of serendipity. In the late 1990s, Harvard immunologist Laurie Glimcher, M.D., knocked out the gene for a transcription factor in mice to study its effect on immunity and found that the mouse embryos died in utero. She suspected a heart defect and asked Baldwin to take a look. It turned out that the mice didn’t form aortic or pulmonary valves.

Since that discovery, Baldwin and colleagues have found that the gene for this “nuclear factor of activated T cells” (NFATc1) is expressed not only in the subset of endothelium that will become endocardium, but also in the particular endocardial cells that will become the heart valve.

By fusing the gene for a fluorescent protein to the portion of the genome that regulates expression of the NFATc1 gene and then inserting this “marker” into mouse embryos, the investigators can now track – by their glow – cells that are destined to make up the heart valve, isolate them for in vitro studies, and even use the system to understand what factors are essential for heart valve formation.

“So we think we’ve got the building blocks; now we’ve got to figure out how to put them together and get them to do what they’re supposed to do,” Baldwin says.

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