Loss-of-function studies in the mouse have shown that the MADS box transcription factor MEF2C and the basic helix-loop-helix transcription factor dHAND are required for normal cardiac morphogenesis. Members of the MEF2 family of transcription factors bind a conserved A/T rich DNA sequence associated with most cardiac muscle structural genes. The overall goal of this proposal is to understand the mechanism by which MEF2C directs cardiac specific gene expression.
The specific aims of this proposal are: 1.) To identify cardiac muscle specific cofactors for MEF2C; 2.) To determine whether MEF2C interacts directly with dHAND; 3.) To intercross MEF2C and dHAND mutant mice in order to test for genetic interactions between these cardiogenic regulators. MEF2C cofactors will be identified using two-hybrid protein interaction screens and expression library screening. The ability of MEF2C to activate transcription in collaboration with dHAND or other cofactors will be evaluated using cardiac specific gene regulatory regions. These studies should yield important insights into transcriptional control of cardiac morphogenesis.
