Control of Cardiac and Limb Development by the bHLH Transcription Factors DHAND and eHAND
McFadden, David Glenn
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Members of the basic helix-loop-helix (bHLH) transcription factor family regulate the specification and differentiation of multiple cell lineages during embryonic development. The bHLH proteins dHAND and eHAND are expressed in complimentary and overlapping patterns during embryogenesis, and gene knockout studies have demonstrated that dHAND and eHAND null embryos die from defects in right ventricular and placental development, respectively. Therefore, we have investigated three aspects of HAND gene biology. Firstly, in order to determine the mechanisms that establish chamber identity during cardiac development, we have identified a transcriptional enhancer that controls dHAND expression in the embryonic right ventricle, and demonstrated that activity of this element depends on paired binding sites for the GATA family of zinc-finger transcription factors. Secondly, we have generated floxed alleles of murine eHAND in order to investigate the role of eHAND during heart formation. These studies have identified a novel role for eHAND during cardiac valve formation, and demonstrated genetic redundancy of HAND genes during mammalian cardiac morhpogenesis. Finally, we have utilized tissue culture assays and transgenic mice to investigate the mechanisms by which dHAND regulates transcription of downstream target genes. These results suggest that dHAND and eHAND may regulate gene expression independently of direct DNA binding and transcriptional activation.