Congenital heart defects are the most common developmental abnormalities in humans, affecting approximately one percent of the population. The Tetralogy of Fallot is the most common cyanotic congenital heart disease and outflow tract defects as a group comprise the majority of cyanotic congenital heart disease. Recent research has implicated a population of specialized cells arising in the pharyngeal mesoderm, termed the secondary, or anterior heart field (AHF) in normal right ventricular, septal, and outflow tract development. Recent studies have also suggested that the transcription factor MEF2C is required for normal right ventricular and outflow tract development. This proposal focuses on the role of MEF2C in the AHF and its derivatives. The Black laboratory has recently created mice with conditional inactivation of mef2c in the AHF and observed that half of these mice die of outflow tract and ventricular septal defects that mimic a spectrum of human diseases.
For specific aim 1, we will characterize the phenotype of these mice and seek to define the mechanisms by which loss of MEF2C in the anterior heart field leads to the observed defects. Because MEF2C has been implicated as an important mediator of cellular differentiation in the embryo, we hypothesize that the defects observed result from a defect in differentiation in the AHF. We will test this hypothesis by examining the expression of various markers of differentiation in the AHF and its derivatives.
For specific aim 2, we will identify transcriptional targets of MEF2C in the AHF and its derivatives. We will use microarrays to study differences in gene expression patterns in the AHF, pharyngeal mesoderm, outflow tracts and right ventricles of wild-type mice and AHF-specific mef2c knockout mice at multiple time points in development. Finally, for specific aim 3, we will examine the upstream regulators of mef2c expression. Specifically, we will investigate the mechanism by which the LIM homeodomain protein ISL1 activates mef2c expression in the AHF. These experiments are expected to provide insight into the genetic programs that control outflow tract and right ventricular development and to permit a mechanistic understanding of these common human congenital heart diseases. Such an understanding may eventually permit development of targeted diagnostic and therapeutic strategies.
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