Using a sophisticated approach to alter gene activity in the embryo, scientists have identified a potential culprit for one of the most common human congenital heart malformations, AVCD (atrioventricular canal defect). As Dr. Kai Jiao and colleagues report in the October 1 issue of Genes & Development, proper expression of a single gene, called Bmp4, is essential for normal mouse embryonic heart development – even a 50% reduction leads to AVCD-like defects.
In its most severe form, AVCD is characterized by a large hole in the wall (the septum) that partitions the heart into upper and lower chambers (atria and ventricles, respectively). This defect disrupts the unidirectional flow of blood through the heart, allowing oxygen-rich blood traveling through the left chambers to re-enter the right chambers. The mixture of oxygenated and deoxygenated blood in the right chambers increases the overall volume of blood that the right ventricle must pump to the lungs. This increased blood volume taxes both the heart and lungs, causing heart enlargement, high blood pressure, and, eventually, pulmonary blood vessel damage (i.e. lung disease).
Dr. Jiao and colleagues now show that the reduced expression of Bmp4 may underlie AVCD.
Dr. Hogan, the senior author, now at Duke Medical Center, says: "We quessed that Bmp4 was critical for heart development more than 10 years ago because it is expressed there at high levels. But the gene is also needed by the embryo very early, before the heart has formed. Dr. Jiao hit on the idea of knocking the Bmp4 gene out just in the embryonic heart muscle (cardiomyocytes), leaving it intact everywhere else. What is more, he manipulated the system, using 'conditional tissue specific gene inactivation', so that Bmp4 activity could be titered down to different levels."
Dr. Jaio observed a direct correlation between the level of Bmp4 activity and the ability of the septum to correctly partition the upper and lower heart chambers – what the researchers call "atrioventricular septation": the less Bmp4 present in cardiomyocytes, the more severe the septation defect.
By varying the level of Bmp4 expression, Dr. Jiao and colleagues were able to recapitulate the entire spectrum of defects seen in AVCD patients. They found relatively mild septation deformities in mice whose cardiomyocytes had slightly less-than-normal levels of Bmp4, while mice whose cardiomyocytes were completely devoid of Bmp4 displayed severe AVCD --making these mice useful models for AVCD research.
The researchers note that mice with Bmp4-deficient cardiomyocytes are, in fact, the first and only genetic model with AVCD as its primary defect.
Since AVCD is a common feature of Down syndrome, these mice will also be useful to study the cardiac defects associated with Down syndrome – perhaps even more so than existing Down syndrome models. While the classic animal model of Down syndrome (Trisomy 16 mice) does effectively portray many aspects of this disease, it does not wholly recapitulate the range of cardiac defects seen in Down syndrome patients. Mice with Bmp4-deficient cardiomyocytes do.
Dr. Hogan observes, "Knocking down genes specifically in some heart cells and not in others, and at different times, is becoming an increasingly important tool. Dr Jiao, as well as scientists here at Duke Medical Center, are using this approach to alter the levels of other genes besides Bmp4. As the big picture emerges it may reveal new insights into congenital heart malformations and perhaps ways to treat or prevent them."
Dr Kai Jiao continues his investigations at Vanderbilt University Medical Center.
The above post is reprinted from materials provided by Cold Spring Harbor Laboratory. Note: Content may be edited for style and length.
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