The regulatory mechanisms that control differential gene expression and morphogenesis of the atria and ventricles of the developing heart are not well defined. Calcineurin A signaling and Nuclear Factor of Activated T-cell (NFAT) activation are associated with altered gene expression in adult cardiac hypertrophy characterized as reactivation of fetal ventricular gene expression. This regulatory mechanism is hypothesized to be conserved in the initial activation of ventricular-specific gene expression in the embryo. Calcineurin- and NFATs are expressed in the mouse embryo consistent with a role in regulating heart chamber-specific gene expression. The importance of NFAT activity in heart chamber development was examined in mice with targeted mutation of nfatc3 and nfatc4. Loss of both NFATc3 and NFATc4 together results in embryonic death between E10.5 and 11.0 with defects in heart morphogenesis. This observation is consistent with a critical role for NFATs in cardiovascular development. The hypothesis is that calcineurin signaling through NFAT activation regulates fetal ventricular gene expression and contractile function. Mechanistic experiments will be performed in chicken and mouse embryos taking advantage of the strengths of each system. Gene targeting and transgenesis in mice will be used to determine the effects of reduced NFAT activity on cardiac morphogenesis and fetal ventricular gene regulation. Adenovirally mediated gene transfer will be used to examine cardiac function in chicken embryo hearts with increased or decreased calcineurin signaling.
The Specific Aims are: 1) Determine if heart chamber-specific gene expression and/or morphogenesis is compromised in nfatc3/c4 mutant mice. 2) Manipulate calcineurin signaling and NFAT activation in chicken embryos with cardiac-specific adenovirus infection. 3) Identify -myosin heavy chain ( -MyHC) regulatory sequences controlled by calcineurin signaling and NFAT activation in the fetal ventricles and adult hypertrophic cardiomyocytes. Together the combination of genetic and experimental embryological approaches will thoroughly examine the role of calcineurin signaling and NFAT activation in ventricular morphogenesis and gene expression. Congenital heart malformations with genetic or teratological origins often include hypomorphism of the ventricles. Thus, the identification of signaling pathways involved in ventricular myocardial development and function has potential importance in the understanding and treatment of congenital heart disease.
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