Muscular dystrophies are debilitating diseases that affect about one out of every 3500 live male births. Several therapeutic strategies for muscular dystrophy are aimed at the capacity of satellite cells or other muscle associated stem cells to repair damaged muscle fibers. Importantly, recent evidence has shown that the regulatory pathways functioning during muscle regeneration share many common features with the myogenic program that functions during skeletal muscle development. Thus, the long term objective of the studies proposed here is to define fully the transcriptional pathways governing skeletal muscle development, regeneration, and repair. One family of transcription factors that plays a key role in skeletal muscle development is the myocyte enhancer factor 2 (MEF2) family. MEF2 proteins function as part of a combinatorial transcriptional complex with members of the MyoD family of basic helix-loop-helix (bHLH) proteins, which are essential for muscle specification and differentiation during development and also play critical roles in satellite cell proliferation and differentiation. The studies proposed here will define the transcriptional regulation and genetic function of the mef2c gene in skeletal muscle. Because MEF2 transcription factors play an essential role in muscle differentiation, it is important to define the regulation and function of these genes during muscle development. A better understanding of these developmental pathways is essential for the development of therapies based on increasing regenerative capacity in skeletal muscle. This study will address the following two specific aims: 1. To determine the function of mef2c in skeletal muscle. Using conditional targeting approaches in mice, the mef2c gene has been specifically ablated in skeletal muscle. The development, function, and regenerative capacity of skeletal muscle without mef2c will be analyzed using histology, molecular markers and analyses of muscle function. Downstream targets will be identified by microarray analyses. 2. To define the regulators of mef2c transcription in skeletal muscle. Recently, a small enhancer and promoter fragment from the mef2c gene that is sufficient to direct expression exclusively to skeletal muscle in transgenic mice was identified. The studies proposed here will define c/s-acting elements that are required for expression in transgenic mice and will identify the trans-acting factors that regulate mef2c.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR052130-04
Application #
7485046
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
2005-08-15
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
4
Fiscal Year
2008
Total Cost
$309,708
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Rojas, Anabel; Schachterle, William; Xu, Shan-Mei et al. (2010) Direct transcriptional regulation of Gata4 during early endoderm specification is controlled by FoxA2 binding to an intronic enhancer. Dev Biol 346:346-55
Rojas, Anabel; Schachterle, William; Xu, Shan-Mei et al. (2009) An endoderm-specific transcriptional enhancer from the mouse Gata4 gene requires GATA and homeodomain protein-binding sites for function in vivo. Dev Dyn 238:2588-98
Kang, Jione; Nathan, Elisha; Xu, Shan-Mei et al. (2009) Isl1 is a direct transcriptional target of Forkhead transcription factors in second-heart-field-derived mesoderm. Dev Biol 334:513-22
De Val, Sarah; Black, Brian L (2009) Transcriptional control of endothelial cell development. Dev Cell 16:180-95
De Val, Sarah; Chi, Neil C; Meadows, Stryder M et al. (2008) Combinatorial regulation of endothelial gene expression by ets and forkhead transcription factors. Cell 135:1053-64
Rojas, Anabel; Kong, Sek Won; Agarwal, Pooja et al. (2008) GATA4 is a direct transcriptional activator of cyclin D2 and Cdk4 and is required for cardiomyocyte proliferation in anterior heart field-derived myocardium. Mol Cell Biol 28:5420-31
Black, Brian L (2007) Transcriptional pathways in second heart field development. Semin Cell Dev Biol 18:67-76
Verzi, Michael P; Agarwal, Pooja; Brown, Courtney et al. (2007) The transcription factor MEF2C is required for craniofacial development. Dev Cell 12:645-52
Heidt, Analeah B; Rojas, Anabel; Harris, Ian S et al. (2007) Determinants of myogenic specificity within MyoD are required for noncanonical E box binding. Mol Cell Biol 27:5910-20
Jaehnig, Eric J; Heidt, Analeah B; Greene, Stephanie B et al. (2006) Increased susceptibility to isoproterenol-induced cardiac hypertrophy and impaired weight gain in mice lacking the histidine-rich calcium-binding protein. Mol Cell Biol 26:9315-26