The outflow tract of the embryonic heart contributes to the formation of the aortic and pulmonary artery. Defects in outflow tract development result in severe congenital heart defects such as persistent truncus arteriosus and double outlet right ventricle. Similarly, atrio-ventricular (A-V) cushions contribute to the formation of the mitral and tricuspid valves as well as to the septa of the adult heart. Abnormalities in A-V cushion development can result in severe congenital heart defects such as A-V canal or tricuspid and mitral valve atresias. Understanding how the outflow tract forms and the A-V cushions develop is therefore critical to understanding the development of many congenital heart defects. Classic studies have demonstrated the requirement of cardiac neural crest cells (CNCC) in the septation of the single outflow tract into the aortic and pulmonary arteries. More recent studies have provided new insight into the development of the myocardium of the outflow tract of the heart. These studies demonstrate the existence of heart precursor cells that are added to the outflow tract and right ventricle. Our preliminary data suggests that the Shh signaling pathway is critical for these """"""""anterior heart field"""""""" (AHF) cells as well as for migratory CNCC during outflow tract formation and septation. In addition, Shh appears to be required for A-V cushion formation and therefore valve development. Loss of the Shh signal results in a single outflow tract (pulmonary artery atresia) and a single A-V valve. We propose that the cardiac defects seen in Shh mutants are due to abnormal development of both CNCC and the AHF during outflow tract development as well as abnormal endocardial cushion formation during valve formation. We propose examining the cell autonomous requirement for hedgehog signaling within AHF and CNCC in the coordinated development of the outflow tract using a Cre/LoxP approach. Similarly we will test the cell autonomous requirement of hedgehog signaling during A-V valve formation using genetic manipulations in the mouse.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086853-03
Application #
7567524
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2007-01-01
Project End
2010-12-31
Budget Start
2009-01-01
Budget End
2009-12-31
Support Year
3
Fiscal Year
2009
Total Cost
$390,000
Indirect Cost
Name
Duke University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Goddeeris, Matthew M; Schwartz, Robert; Klingensmith, John et al. (2007) Independent requirements for Hedgehog signaling by both the anterior heart field and neural crest cells for outflow tract development. Development 134:1593-604