A new Vanderbilt University study has identified a chemical signal that plays a critical role in forming the heart, which could lead to new strategies to combat congenital heart defects.
In the initial stage of development, called gastrulation, the fertilized egg undergoes a marvelous and complex transformation from a ball of identical cells into an embryo with a distinct shape and a number of different cell types. During this transformation, cells move to specific locations where they begin their transformation into skin, muscle, bone, heart, nerve and other specialized cell types.
The study, published in the March issue of the journal Developmental Cell, identifies a chemical signal which directs cells destined to become cardiac cells to the proper location for their transformation.
“In the last few years, we and others have uncovered a number of pathways that direct and regulate global cell movement, but this is the first pathway that we have found that controls the movement of a discrete group of cells that form rudimentary organs while leaving the rest of the cells largely unaffected,” says Lillianna Solnica-Krezel, the professor of biological sciences at Vanderbilt who directed the study.
Heart defects are the most common type of birth defect. Each year, more than 30,000 babies in the United States are born with congenital heart defects. Currently, the causes of these defects are largely unknown. However, many of them involve malformations that can be traced back to the earliest stages of heart formation and so may be the result from breakdowns in the control of precursor heart cell motion. So increased understanding of the chemical signals that control these motions may shed new light on the underlying causes of these defects and could suggest new methods to diagnose them.
The research was conducted using zebrafish, a small tropical fish that has become an important animal model for studying the development of vertebrates, animals with backbones. Zebrafish have characteristics that make them ideal subjects. They lay eggs that are transparent and develop outside the body, allowing scientists to observe changes directly as they take place. Zebrafish embryos develop rapidly, proceeding from fertilization to hatching in only three days. The fish are also easy and inexpensive to raise, so scientists can keep thousands of them in a laboratory. The zebrafish genome is currently being sequenced, which allows researchers to employ the powerful tools of genomics to unravel the complex molecular processes involved in development.
Solnica-Krezel’s team discovered that a protein called Apelin acts as a chemical signal for heart cell formation. Apelin is a known chemokine, meaning that it is involved in a process called chemotaxis, the motion of a cell toward or away from an increasing concentration of a particular chemical. For example, chemokines are typically released at sites of infection to guide white blood cells to the area. Apelin pairs with a G protein-coupled receptor. GPCRs are one of the largest families of membrane proteins. They sit on the cell membrane and transmit signals from outside the cell to its interior. There are about 1,000 GPCRs in the human body and, in addition to their role in the immune system, they are involved in neuron migration in the central nervous system and play critical roles in sensory systems, including vision and smell. Apelin binds to a GPCR named AGTRL1B.
“This fills a big gap in our understanding of gastrulation, which is the ‘mother of all movements,'” says Solnica-Krezel. “Cell movement in gastrulation looks very similar to cell movement during chemotaxis, so we have expected for years that G-coupled protein receptors and chemokines must be involved.”
The relationship between Apelin/AGTRL1B and the precursor cardiac cells is extremely strong and specific. This is illustrated by the fact that, when the researchers block the activity of the receptor, the embryo develops normally with one exception: There is a hole in the place where the heart should be.
According to the researchers, this specificity makes it likely that other chemokine/GPCR pathways may control the movement of precursor cells of other types, such as nerves, muscle and bone.
Co-authors of the paper are Vanderbilt graduate student Xin-Xin I. Zeng, research associate Thomas P. Wilm and research fellow Diane S. Sepich. The research was funded by the National Institutes of Health.
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