Cardiovascular defects represent the largest class of congenital anomalies in the United States and efforts to prevent these defects require a greater understanding of the genetic pathways controlling the formation of the heart and vascular systems. Likewise, efforts to regenerate cardiac tissue, or to selectively inhibit or induce the growth of the vasculature require a deeper understanding of the embryonic programs that control the formation of these lineages. The long-term goal of these studies is to define the genetic pathways that control the formation of the cardiovascular system. This proposal focuses on the transcriptional requlation and function of the transcription factor MEF2C in cardiac and vascular development. Mef2c is expressed in the heart and vascular endothelium shortly after the initial specification of myocardial cells in the precardiac mesoderm and in the vasculature shortly after the initiation of vasculogenesis. Mef2c is an early factor involved in differentiation and may be a direct transcriptional target of lineage specific determination factors. Targeted disruption of mef2c in the mouse results in embryonic lethality at midgestation and these mice display profound cardiac and vascular defects. However, it is not clear whether both of these defects are due to a primary requirement for mef2c in that tissue. Using a conditionally targeted allele of mouse mef2c, the work proposed in these studies will remove mef2c function specifically in endothelial cells using Tie2-Cre and will use a novel anterior heart field transcriptional enhancer defined in this application to direct Cre-mediated excision of mef2c in the anterior heart field. The work proposed here will also define the regulation of two novel transcriptional enhancers from the mouse mef2c gene, one of which is exclusively expressed in the vascular endothelium and the other that is restricted only to the anterior heart field, using transgenic approaches in mice.
The specific aims of this proposal are: 1) To determine the requirement of mef2c function in the anterior heart field and in the vascular endothelium. This proposal is designed to test the hypotheses that the cardiac abnormalities observed in mef2c null mice are due to primary defects in anterior heart field development and that mef2c function is required in endothelial cells for vascular development. 2) To define the requlation of mef2c in the anterior heart field and the vascular endothelium. These studies will identify the transcriptional regulators that confer spatial restriction to the mef2c anterior heart field enhancer and will identify the upstream regulators of a vascular endothelial enhancer from mef2c. 3) To determine the regions of the adult heart derived from the mef2c-expressing cells in the anterior heart field. ? ?
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