Formation of a functional, multi-chambered heart involves a complex regulatory network of signaling molecules and transcription factors. Perturbations at any step in this process often result in severe morphological and/or functional defects. Thus, understanding the function of cardiac developmental control genes will reveal important clues into the genetic basis of congenital heart malformations. A transcription factor that plays an important role in cardiac muscle development is the MEF2 protein family. Loss-of function mutations in rnef2 in flies and in mice disrupt the appropriate development of cardiac muscle. Hence, a comprehensive in vivo analysis of mef2 will lead to a better understanding of the genetics and molecular mechanisms of heart development. In vertebrates, MEF2 is encoded by four genes, mef2a,-b,-c, and -d that are coexpressed in muscle and non-muscle lineages and whose functions in vitro are largely interchangeable. However, targeted mutations in mice have revealed distinct roles for mef2a and mef2c in cardiac development, mef2a null mice exhibit a post-natal cardiomyopathy with severe cytoarchitectural and mitochondrial defects in the multi-chambered heart whereas mef2c mutant mice display altered cardiac looping morphogenesis during embryogenesis. Given the distinct cardiac phenotypes, the mechanisms by which closely related genes within a multigene family uniquely regulate cellular differentiation in vivo will be explored. Because the mef2a knockout mice represent a potential connection to human cardiac disease a thorough developmental and genetic analysis will be initiated. The proposed research will address these questions using gene targeting and transgenic approaches in mice.
The specific aims are: 1) to generate a conditional knockout for the mef2a gene to determine the tissue-specific and temporal requirement for mef2a in cardiac muscle cells and the role of mef2a in the adult heart, 2) to create knock-in alleles for the mef2a and mef2c genes to examine possible functional redundancy between these two vertebrate mef2 genes, and 3) to dissect the molecular mechanisms of the post-natal cardiomyopathy in mef2a knockout mice by identifying and characterizing genes dysregulated in mutant hearts. The elucidation of MEF2-dependent transcriptional pathways in vivo will be an important step in the development of genetic strategies to treat cardiovascular disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cell Development and Function Integrated Review Group (CDF)
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Schramm, Charlene A
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Boston University
Schools of Arts and Sciences
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Farrell, Emily; Armstrong, Annie E; Grimes, Adrian C et al. (2018) Transcriptome Analysis of Cardiac Hypertrophic Growth in MYBPC3-Null Mice Suggests Early Responders in Hypertrophic Remodeling. Front Physiol 9:1442
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