| 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 10th
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.
For
a printer friendly version of this release,
click
here.
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