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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073304-02
Application #
6804035
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Schramm, Charlene A
Project Start
2003-09-30
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$323,000
Indirect Cost
Name
Boston University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
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
Medrano, Jose L; Naya, Francisco J (2017) The transcription factor MEF2A fine-tunes gene expression in the atrial and ventricular chambers of the adult heart. J Biol Chem 292:20975-20988
Desjardins, Cody A; Naya, Francisco J (2017) Antagonistic regulation of cell-cycle and differentiation gene programs in neonatal cardiomyocytes by homologous MEF2 transcription factors. J Biol Chem 292:10613-10629
Naya, Francisco J; Wang, Da-Zhi (2016) (MYO)SLIDing Our Way Into the Vascular Pool of Long Noncoding RNAs. Arterioscler Thromb Vasc Biol 36:2033-4
Desjardins, Cody A; Naya, Francisco J (2016) The Function of the MEF2 Family of Transcription Factors in Cardiac Development, Cardiogenomics, and Direct Reprogramming. J Cardiovasc Dev Dis 3:
Clark, Amanda L; Maruyama, Sonomi; Sano, Soichi et al. (2016) miR-410 and miR-495 Are Dynamically Regulated in Diverse Cardiomyopathies and Their Inhibition Attenuates Pathological Hypertrophy. PLoS One 11:e0151515
Estrella, Nelsa L; Desjardins, Cody A; Nocco, Sarah E et al. (2015) MEF2 transcription factors regulate distinct gene programs in mammalian skeletal muscle differentiation. J Biol Chem 290:1256-68
Estrella, Nelsa L; Clark, Amanda L; Desjardins, Cody A et al. (2015) MEF2D deficiency in neonatal cardiomyocytes triggers cell cycle re-entry and programmed cell death in vitro. J Biol Chem 290:24367-80
Feng, Yi; Desjardins, Cody A; Cooper, Olivia et al. (2015) EGR1 Functions as a Potent Repressor of MEF2 Transcriptional Activity. PLoS One 10:e0127641
Clark, Amanda L; Naya, Francisco J (2015) MicroRNAs in the Myocyte Enhancer Factor 2 (MEF2)-regulated Gtl2-Dio3 Noncoding RNA Locus Promote Cardiomyocyte Proliferation by Targeting the Transcriptional Coactivator Cited2. J Biol Chem 290:23162-72

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