Feb. 19, 1999 Boston, MA -- How an organ develops and acquires its characteristic shape is a fundamental question in biology. Now a team of Harvard Medical School researchers led by Howard Hughes investigator Connie Cepko has gotten to the heart of the problem?literally. They have identified a gene called Irx-4 that opens doors to understanding how the heart chambers form. Their findings appear in the February 19 Science.
Scientists knew that certain genes were expressed either in the future ventricles (the lower chambers) or the future atria (the upper chambers) of the developing heart. But no one really knew how these genes? impact remained confined to their respective regions?the ventricles or the atria?or whether their restricted expression reflected a role in setting up the heart chambers.
With the discovery of Irx4, researchers will now be able to ask these questions. Cepko, HMS professor of genetics, postdoctoral fellow Zheng-Zheng Bao, and their colleagues showed that Irx4 can induce the expression of a ventricle-specific gene, ventricle myosin heavy chain-1 (VMHC1), and prevent the expression of an atrium-specific gene, atrial myosin heavy chain-1 (AMHC1), suggesting that Irx4 works to maintain the boundaries between the heart chambers.
"Before Irx4, there was no way into the problem of how these chambers get set up. Irx-4 now gives us a tool to understand the broader process of chamber specification or chamber formation. We just didn't have a molecule before to do that," said Cepko.
Irx4 was identified because the researchers were interested in a family of genes in the fruit fly involved in setting up compartment boundaries in several organs. When the gene was found in the chick, its striking expression pattern in the heart was hard to ignore: from an early stage in development, Irx4 was present very specifically in the future ventricle region.
The presence of Irx4 in the ventricle suggested that it may influence the expression of other chamber-specific genes. Until now, no other genes were known to regulate VMHC1 or AMHC1. Using retroviral vectors to deliver the Irx4 gene to the hearts of chick embryos, the scientists asked whether they could change how VMHC1 or AMHC1 behaved. They found that Irx4 not only turns on VMHC1, but that it blocks expression of AMHC1. This suggested to Cepko and colleagues that Irx4 may work by allowing VMHC1 to be expressed in the ventricle while at the same time preventing AMHC1 from appearing there.
This role of restricting chamber-specific genes to their respective regions may be conserved through evolution, because the researchers have also found Irx4 to be localized in the ventricles of mice and zebrafish.
Studying Irx4 may also shed light on the cause of certain heart defects. "If we have a full understanding of heart development and function, we will better be able to deal with heart disease," said Cepko.
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