DESCRIPTION (provided by applicant): Congenital heart defects (CHDs) are the #1 birth defect in the United States and the leading non-infectious cause of death in children. Following the colonization of extracardiac cell populations, the primitive heart tube undergoes septation and valvar formation to convert it into a four-chambered heart. These extracardiac cell populations include the anterior heart field, cardiac neural crest and epicardially-derived cells. Although many markers exist to follow the migration of both the EPDCs and cardiac NC-derived cells into the mammalian heart, none of these markers specifically mark only these cell subpopulations and furthermore, all of these markers are turned off as soon as the cells reach the heart - making the role and function of these cells once they reach the heart elusive. This is a particular drawback when considering the ultimate role of the outflow tract mesenchymal cushion cells within outflow tract morphogenesis and pathogenesis of CHDs. Our study of the transcriptional regulation of the broadly expressed gene, periostin has revealed a 3.9kb transcriptional regulatory module that drives expression in the peripheral nerves and a novel subpopulation of "outflow tract-derived cells" (OFTDCs). Furthermore, we find that descendents of the OFTDCs replace many of the initial conommcal and atrioventricular (AV) cushion mesenchymal cells just prior to and during septation and valvar formation. These novel data suggest a new paradigm for heart development in which the two limbs of the heart may interact through their cushions and that many of the non-cardiomyocytes of the developing mouse heart transiently express the 3.9kb-periostin module. Thus, we hypothesize that there is cell exchange between the outflow track and AV cushions and that the mature outflow and AV valves are ultimately derived from this migratory endothelial-derived OFTDC subpopulation of cushion cells. These results present a radical new outlook on cardiogenesis, where the majority of the mature heart's mesenchymal cells arise from a small subpopulation of cells within the embryonic outflow tract itself, and not from extra-cardiac sources as previously believed. To test this novel hypothesis, we propose four interrelated aims: Aim 1 will determine the ultimate fate of the OFTDCs in the fetus, newborn and adult mouse. Aim 2 will determine the origin of the OFTDCs. Aim 3 will isolate the 3.9kbperi-enhanced green fluorescent protein (EGFP) expressing OFTDCs and identify differentially-expressed genes. Aim 4 will determine the requirement of the OFTDCs to cushion development and heart morphogenesis by genetically ablating each cell as it transiently expresses the 3.9kb periostin promoter/enhancer.
|Effective start/end date||7/1/04 → 5/31/08|
- National Institutes of Health: $333,915.00
- National Institutes of Health: $357,818.00
- National Institutes of Health: $346,119.00
- National Institutes of Health: $370,443.00