September 9, 2004

OutFoxed! New Research May Redefine Late-Stage Cardiac Development
Penn Researchers Inactivate the Foxp4 Transcription Factor and Their Findings May Provide
New Insight Into the Causes of Congenital Heart Disease

(Philadelphia, PA) -- According to the American Heart Association, congenital cardiovascular defects, such as congenital heart disease (CHD), are present in about one percent of live births and are the most common malformations in newborns. A team of University of Pennsylvania School of Medicine researchers, led by Edward E. Morrisey, PhD, Associate Professor of Medicine, have been investigating how the heart develops from its earliest stages of development to its late stages, with the hope of learning why some hearts don’t develop correctly. Dr. Morrisey’s latest finding – to be published in the September 10^th issue of Science – may redefine current models of how the heart develops in mammals. “Understanding the earliest steps in heart development gives us insight into the possible genetic causes of the dramatic heart defects exhibited by so many newborn babies, “ says Morrisey.

During normal embryonic development in mammals, pre-cardiac cells form the bilateral cardiac primordia – two symmetrical, tube-shaped regions located on both sides of the early embryo. As cardiac development progresses, these two regions fuse, forming one large tube, which, in turn, further develops into the four-chamber heart.

Using genetically engineered mice, Penn researchers successfully inactivated the Foxp4 binding protein, which resulted in the inability of the bilateral tubes to fuse. They found that each region of pre-cardiac cells still developed into a single tube, and then further developed into a four-chamber heart. This resulted in the mouse embryos developing two, four-chambered hearts exhibiting most aspects of advanced heart development. Eventually these embryos succumbed due to the lack of correct blood flow with two hearts pumping into the same set of blood vessels.

Foxp4 belongs to a class of DNA binding proteins called transcription factors that turn other genes on and off. Interestingly, Foxp4 is not expressed in heart muscle cells themselves but rather in the primitive gut tube, which will develop into the stomach and intestines. In the early mammalian embryo, the gut tube helps direct the fusion of the two tubes of pre-cardiac cells into one tube. Dr. Morrisey thinks that expression of Foxp4 in the gut tube may be responsible for this lack of fusion: “Other mutations in genes expressed in the gut tube have led to similar results in simpler organisms such as zebrafish. What is remarkable about Foxp4 mutant mice is that their hearts develop to such a late stage. We have never been able to determine in mammals whether fusion of the bilateral heart tubes was required for later stages of development including formation of all four-heart chambers. Now we know it’s not necessary."

Another aspect of the work that is remarkable is that both of the hearts that form in Foxp4 mutant embryos show the same ability to distinguish left and right “sidedness”. Many organs in the mammalian body have distinct left and right sides such as the heart and lung. In Foxp4 mutant embryos, both hearts show the correct “sidedness” regardless of whether they were on the right or left side of the embryo.

The researchers suggest this work may be crucial in determining what gene mutations might lead to congenital cardiovascular defects. Cardiac development is conserved in mammals so defects in early cardiovascular development may lead to malformations in the human heart. “Although there have been no substantiated reports of humans born with two hearts, our understanding of how this very early process of fusion of the two bilateral cardiac primordial is regulated should provide a better understanding of many aspects of later heart development including those that are directly linked to congenital heart disease” says Morrisey.

Other Penn researchers contributing to this study are Shanru Li, Deying Zhou and Min-Min Lu. This study was funded by grants from The National Institutes of Health and the American Heart Association.

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PENN Medicine is a $2.7 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System (created in 1993 as the nation’s first integrated academic health system).

Penn’s School of Medicine is ranked #3 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report’s most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

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This release is available online at http://www.uphs.upenn.edu/news/News_Releases/sep04/cardiacdev.htm