Princeton research takes asymmetry to heart

Rebecca Burdine

Rebecca Burdine (left), assistant professor of molecular biology, and graduate student Jessica Rowland use zebrafish to study why heart defects occur and what can be done to prevent them.

Ask most people to draw a heart and they will make a symmetrical drawing with two equal sides. But the human heart is far from symmetrical. The right side is slightly smaller, built for pumping blood into the nearby lungs, while the left side is larger and made for propelling blood throughout the body. When defects in this asymmetric development occur, the result is often fatal. Congenital heart defects are the most common types of birth defects, affecting nearly 40,000 infants born in the United States each year.

Jessica Rowland, a graduate student in Princeton’s Department of Molecular Biology, is studying the genes that orchestrate this development of the two very different sides of the heart. What Rowland and her adviser, Rebecca Burdine, assistant professor of molecular biology, learn could aid our understanding of why heart defects occur and what we can do to prevent them.

The researchers use zebrafish as a model organism because the fish reproduce quickly and it is easy to manipulate their genes — knocking out their activity, or, alternatively, turning up their expression — then observe the outcome. In a room reminiscent of a pet store, floor-to-ceiling aquariums provide homes for roughly 15,000 of the silver-colored, half-inch-long fish.

The heart starts out as two symmetric clumps of cells, one on each side of the body. During embryonic development, these cells come together in the middle of the embryo and fuse to create a structure called the cardiac cone. Cells on the left side of this cone are exposed to a set of events called the Nodal signaling pathway. In zebrafish, the Nodal gene is called southpaw, because it is expressed only on the left side of the heart. This gene orchestrates the process as the entire cone rotates, tilts and elongates into a tube that extends asymmetrically to the left to take shape as the heart.

Rowland is exploring how expression of southpaw, specifically on the left, sets off other gene pathways that act downstream to cause the cells to migrate and elongate into the asymmetrically positioned tube. Rowland has a National Science Foundation pre-doctoral fellowship and the research is funded by the National Institute of Child Health and Human Development.

In a recent study, Rowland compared heart cells in which expression of the southpaw gene was either turned up or turned off. The researchers found that turning up southpaw expression led to the turning on of a handful of specific gene pathways. “Several of these pathways have to do with cell migration, which makes sense because the heart cells are moving to new locations,” Rowland said. The team is now exploring exactly how these pathways control heart cell migration and development.