Our observations of the heart defect (hdf) null embryo has provided remarkable evidence that the Cspg2 gene (versican) has an unexpectedly important role in the growth and differentiation of the outlet segment (conotruncus) of the heart. We propose to determine the critical role of versican in a region that is a """"""""hot spot"""""""" for clinically important birth defects affecting over one-half of all human live birth heart defects. The conotruncus of the developing outlet forms from a previously unrecognized mesodermal heart field located anteriorly to the primitive ventricle. We propose the Cspg2 gene promotes differentiation and stabilization of the myocardial phenotype as a contractile and inductive signaling tissue in the growing conotruncus. Our hypothesis is that 1) specific functional domains of Cspg2 are required for normal myocardial recruitment in the growing outlet and 2) the programmed loss of the truncus myocardium during the late remodeling stages results from the absence of specific functional domains of Cspg2. An abnormal loss or other variation of versican expression at the early recruitment or later remodeling stages, affects the normal patterns of phenotypic stabilization in the truncus myocardium and results in conotruncal heart defects. We propose the following Specific Aims: 1) To determine the expression patterns of Cspg2 functional domains in the developing conotruncus during (a) early recruitment of the myocardium from the anterior heart field mesoderm (AHF) and during (b) later stages when the truncal myocardium is known to regress; 2) To test the hypothesis that Cspg2 functions to stabilize the conotruncus phenotype by overexpressing Cspg2 in a whole animal transgenic mouse model.; 3) To determine if specific Cspg2 functional domains are required for recruitment and/or stabilization of the conotruncus myocardium's contractile and inductive signalling phenotypes; 4) To determine if specific domains of the Cspg2 protein have a functional role later in contruncal development to remodel the truncus by destabilizing the myocardium for transdifferentiation into a fibrous connective tissue.
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