In a complex organ like the heart, consisting of multiple anatomical structures and various cell types, regulatory networks have been exquisitely designed to integrate numerous signaling pathways and transcription factors. This circuitry is further wired by interweaving multiple members within a given family of transcription factors, with each regulating specific cellular differentiation programs, so that they are activated at precise developmental time points. Perturbations in this finely tuned network can lead to major anatomical or functional abnormalities. Thus, delineating the gene programs regulated by each factor and the temporal relationships within a multi - gene family is essential to our understanding of the physiology and pathology of the heart. Myocyte enhancer factor - 2 (MEF2) is one of the key transcription factor families involved in cardiogenesis. MEF2 is a transcription factor encoded by four genes, mef2a, -b, -c, and -d in vertebrates which exhibit a high degree of sequence and functional similarity. While the transcriptional activities are largely interchangeable in vitro, targeted mutations in mice have revealed dramatically different phenotypes for the mef2 genes. A null mutation in the mef2c gene results in defective cardiac looping during embryonic development, whereas mef2a mutant mice exhibit post - natal cardiac abnormalities including myofibrillar disarray and mitochondrial deficiency. Mutant mef2d mice display alterations in stress - dependent cardiac remodeling. In contrast, mef2b mice are viable. These data suggest that each MEF2 factor has inherently different biological activities by controlling unique gene programs within the developing heart. Given the overt perinatal cardiac abnormalities in mef2a null mice we sought to molecularly characterize this phenotype by gene expression profiling. We identified two novel MEF2A target genes whose products localize to a specialized macromolecular complex known as the costamere. To further dissect the function of MEF2A in cardiac differentiation we want to molecularly dissect a broader subset of MEF2A - dependent genes linked to the costamere. We will also begin to identify unique gene expression signatures of MEF2A and MEF2C in muscle to gain a better understanding of the mechanisms by which two highly related transcription factors control different aspects of cellular differentiation. Finally, since nothing is known regarding the function of MEF2A in mature muscle we want to characterize the role of MEF2A in the adult heart.
The specific aims are: 1) to characterize a newly identified cohort of MEF2A - dependent genes linked to the costamere;2) to identify unique gene expression signatures of MEF2A and MEF2C, and 3) to investigate the role of MEF2A in the adult heart. The molecular dissection of MEF2 - dependent transcriptional pathways will be an important step in the development of genetic strategies to treat cardiovascular disease.

Public Health Relevance

This research will help us understand the genetic mechanisms by which regulatory genes and their pathways are precisely assembled in the formation and function of the heart. Our results will substantially contribute to our knowledge regarding the genetics of congenital cardiac disorders. Given the complex physiology of the heart our findings will also help launch new avenues in the development of pharmacological strategies for the treatment of heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073304-08
Application #
8299115
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
2003-04-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
8
Fiscal Year
2012
Total Cost
$420,271
Indirect Cost
$161,906
Name
Boston University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
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McCalmon, Sarah A; Desjardins, Danielle M; Ahmad, Saad et al. (2010) Modulation of angiotensin II-mediated cardiac remodeling by the MEF2A target gene Xirp2. Circ Res 106:952-60
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Durham, Jennifer T; Brand, Ondra M; Arnold, Michael et al. (2006) Myospryn is a direct transcriptional target for MEF2A that encodes a striated muscle, alpha-actinin-interacting, costamere-localized protein. J Biol Chem 281:6841-9