Malformations of the cardiovascular system account for most of the premature deaths caused by congenital abnormalities. Of these, the majority are congenital heart defects that arise from the abnormal remodeling of the single heart tube into four separate and properly aligned chambers. The cardiac cushions, formed from mesenchymal swellings, within the wall of the embryonic hear tube are fundamentally linked to the process of remodeling. The outflow tract (conotruncal segment) is one of only two regions of the heart where endocardial cushions form to mediate the remodeling process. The importance of understanding the origin and fate of the conotruncal segment and associated cushions is that this site is most likely to be associated with birth defects of the heart in humans and, in fact, is a very common site of malformations that result from a wide variety of experimental perturbations in vertebrate models of congenital heart disease. The primary focus of this project will be to investigate the molecular pathways that lead to the initial formation of the conotruncal cushion segment, determine the factors that link segment formation with cushion mesenchyme formation and the cellular interactions that impart different developmental fates to the cushion-forming segments and, thereby, create a final common pathway for potentially defective heart remodeling. The first Specific Aim is to determine the origin of the conotruncal """"""""outlet"""""""" segment and its mechanism of morphogenesis and is based on five interrelated hypotheses (1) the conotruncal segment is added as a new structure to the distal end of the heart tube from a previously unrecognized anterior heart field; (2) the precardiac cells are recruited into myocardial lineage by the existing myocardium; (3) the premyocardial cells are induced, in part, through the action of bone morphogenic proteins; (4) endocardial cells are recruited by mesodermal cells at the distal boundary of the outflow tract by TGF betas and the proteoglycan neurocan; (5) expression of the heart defect gene is irreplaceably required to sustain/mediate induction of the conotruncal precursor cells and/or stabilize their phenotype into the concentric epithelial architecture of the outflow tract. The second Specific Aim is designed to investigate the molecular links between segment formation and the specific site of cushion mesenchyme induction in the heart tube.
The third aim i nvestigates the relationship between the positional differentiation (fate) of the cushion mesenchyme, invasion of neural crest and myocardialization, an active invasion of myocardial cells into the conal cushions, that is the pivotal morphogenetic mechanism for remodeling the U-shaped heart tube into four chambers.
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