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MEDICINE Mice Yield Clue to Heart Valve DevelopmentModel Could Show How Valve Defects Lead to Heart Failure Standing guard at the exit of each of the heart's four chambers are tiny membranous flaps, the heart valves. In most people, these valves function flawlessly, opening and closing—letting blood out and preventing it from flowing back—all within the space of a single heartbeat. But inborn defects can render heart valves so thick and stiff that blood has a hard time making it out of a chamber. Over time, the heart must pump harder, causing it to enlarge and setting the stage for heart failure. Congenital heart valve defects have led to heart disease in thousands of people and yet, in most cases, their causes have been a mystery. Viruses, drugs, and other environmental factors have been blamed but little is known about which genes may go awry to cause valve defects. Nor is much known about how human heart valves develop normally.
Ben Neel and colleagues have identified proteins that may play a role in heart valve development. Ben Neel, Binbin Chen, and their colleagues have recently identified two genes—one well known, the other a relative newcomer—that may play a role in normal valve development. When one of the genes, which produces the well-studied epidermal growth factor receptor (Egfr), is mutated in mice, it results in thickening of two of the heart's four valves, the aortic and pulmonic valves. The researchers found that mating those mutants with mice carrying a defective version of another gene, Shp2, produces even more striking abnormalities. Most offspring die before birth. Those that survive have massively overgrown aortic and pulmonic valves and develop heart disease as young adults. The findings appear in the March 1 Nature Genetics. So far, people suffering from congenital heart valve disease have not been found to carry mutant versions of the Egfr and Shp2 genes. One possibility is that the pair play such a critical role in normal valve development that a human embryo could not withstand defects—and, indeed, most of the mice double mutants died before birth. In this regard, the mutant mice say more about how normal human valves arise than how they become defective. But Neel, HMS professor of medicine, believes the mice could shed light on what happens once defects develop. "These mice go on to get all the sequelae of aortic stenosis and aortic regurgitation. They get rhythm abnormalities, increased pressure in their heart chambers, and eventually heart failure—and this might explain why these mice drop dead at a premature age," Neel says. "So the real value of the model is to show progressive heart failure from a stenotic lesion."
Among those collaborating on the project were Rod Bronson, Jim Morgan, the Herman Dana professor of medicine, and Binbin Chen, currently at Account4.com in Newton. A Cinderella ProteinNeel did not set out to find a model for heart valve disease. Nor was he seeking a new role for Egfr. Like so many scientific forays, this experiment started in pursuit of an altogether different goal—in this case, a better understanding of Shp2. Although it has become a protein to watch, until recently Shp2 and proteins like it were relegated to the status of cellular housekeepers.Cells regulate protein activity by adding and removing phosphates. Kinases put phosphates on while phosphatases, including Shp2, take them off. Until recently, the phosphatases were thought by many to be simply cleaning up after the kinases, which were believed to hold the regulatory reins. That belief had begun to crumble by the early 1990s, thanks in part to the work of another team of HMS researchers. Lizabeth Perkins, currently HMS assistant professor of surgery at Massachusetts General Hospital, but then working in the lab of Norbert Perrimon, Howard Hughes investigator and HMS professor of genetics, demonstrated that the fly homolog of Shp2, the gene corkscrew, actually enhances the signals put out by another protein during embryonic development. Flies lacking the corkscrew protein did not develop proper heads and tails. Neel and his colleagues went on to show that Shp2 played a similar role in vertebrates.
Compared to the aortic valves of normal mice (see red arrows, top left), those of mutant mice with low Egfr–Shp2 activity are greatly thickened (lower left). Thickening of the valves means the heart has to pump harder, which causes it to enlarge, setting the stage for heart failure. The hearts of the mutant mice are much bigger (lower right) than those of normal mice (top right). Meanwhile, evidence was accumulating that the Shp2 enzyme might be regulating several growth factor pathways. To explore its role, Chen, who was a research fellow in medicine, bred a strain of mice with low levels of Shp2 due to a defective gene and mated them with an already existing mouse strain known to express weakened versions of Egfr. The Egfr-deficient mice exhibit a few quirks such as wavy hair and curly whiskers but are otherwise fairly normal. If Shp2 normally enhanced signals sent by Egfr, then pairing the Egfr and Shp2 mutants should produce offspring with a more severe phenotype. Most of the matings did not produce any viable offspring. But, to the researchers' surprise, the babies that were born looked, for the most part, normal. "That was a real problem for us," Neel says. Working with Rod Bronson, then at Tufts and now director of the mouse pathology core of the Dana–Farber/Harvard Cancer Center, they began scouring organ after organ for defects. When he came to the mouse hearts, Bronson found the aortic and pulmonic valves were "totally abnormal," Neel says. "It's not a subtle phenotype—they're dramatically thickened." And all the mice were affected. Hearts BrokenBut the finding raised a dilemma of its own: the parents of the mice—the Egfr and Shp2 mutant strains—were believed to have normal hearts. Upon closer inspection, it turned out that about 80 percent of the Egfr mice also had variably thickened valves, which had been overlooked for three decades."So that says the Egfr-Shp2 pathway is required for normal aortic valve development," says Neel. As for how the pathway might be working, he speculates that Egfr may act to limit the number of precursor, or endocardial, cells that undergo the necessary transitional steps to become heart valve cells. "If you don't have effective Egfr signaling, you may overtransform," he says. Lack of normal amounts of Shp2 could exacerbate such poor signaling. Although human heart valve defects are not known to be caused by a lack of Egfr and Shp2, Neel thinks the double mutants have relevance for human disease. "There are very few, if any, models of aortic valve disease in rodents," Neel says. "This is a potential model for following pathogenesis in the mouse and, conceivably, testing out drugs—though for the foreseeable future, surgery and valve replacement will be the treatment of choice in people." The benefits of understanding the Egfr-Shp2 pathway could extend to other human diseases. Too much Egfr has been identified as the culprit in many cancers. One way to reduce Egfr activity may be to inhibit Shp2. "Since Egfr and its close relatives, such as Her2-Neu, show increased activity in a large number of human tumors, such as brain, ovarian and lung, a drug that inhibits Shp2 may be therapeutically useful," Neel says. —Misia Landau |
