In this section
Joseph X. DiMario, PhD
Center for Cancer Cell Biology, Immunology, and Infection
Our laboratory investigates several aspects of myogenesis using a variety of paradigms and model systems. Much of our research focuses on the cellular and molecular mechanisms that regulate the development and differentiation of skeletal muscle fibers and their respective phenotypes. We are also exploring the mechanisms that control myogenic cell proliferation versus differentiation in both skeletal and cardiac muscle development.
Molecular and Cellular Control of Muscle Cell Phenotype
Much of our research focuses on the mechanisms that establish and maintain skeletal muscle fiber type diversity during development. Research in our lab is based on avian model systems in which both intrinsic and extrinsic regulation of muscle fiber type is analyzed. Unique muscle cell/nerve co-cultures are generated to explore the cell-cell interactions leading to muscle cell diversity. Direct electrical stimulation of muscle fibers in vitro is also being employed in our studies. Our research indicates that intrinsic differences between myoblasts before overt differentiation leads to diversity in muscle fiber types. Additionally, innervation modulates muscle fiber type and associated fiber type specific gene expression. Published results indicate that protein kinase C (PKC) activity in conjunction with innervation-induced activation of cell signaling mediated by the muscarinic acetylcholine receptor, Gaq, and the 1,4,5 inositol triphosphate receptor 1 (IP3R1) differentially regulate fast versus slow muscle fiber type gene expression in innervated muscle fibers. This signaling culminates in regulation of transcription factors governing expression of the slow myosin heavy chain 2 gene - indicative of the slow muscle fiber phenotype. Our on-going research is focused on the regulatory mechanisms that link innervation, PKC activity, IP3R1 activity, transcriptional regulators, and expression of slow muscle fiber type specific genes.
More recently, we have initiated studies to investigate the molecular mechanisms that control the development of distinct myogenic cell lineages during embryonic mygenesis. These lineages are defined are distinct types of embryonic myoblasts that are committed to the differentiation of diverse, lineage-based, muscle fiber types. The aim of this research is to identify and characterize the molecular regulatory circuitry that establishes these myogenic cell lineages and which thereby establish fast versus fast/slow muscle fiber types, independent of innervation, and dependent of cell lineage commitment.
Regulation of Myoblast Proliferation and Differentiation
During vertebrate myogenesis, myoblast cell populations proliferate and fuse to form multinucleated muscle fibers that express a battery of contractile protein genes. The mechanisms that regulate myoblast cell proliferation versus differentiation involve extracellular signaling via growth factors, their cognate receptors, intracellular signal transduction cascades, and transcriptional regulation of genes associated with cell proliferation. Among these genes is the fibroblast growth factor receptor 1 (FGFR1) gene which is expressed in proliferating myoblasts and down-regulated during differentiation. We are interested in the transcriptional regulation of the FGFR1 gene because its expression is tightly linked to continued myoblast proliferation. Our published findings demonstrate that the FGFR1 gene is positively regulated by the Sp1 transcriptional regulator and negatively regulated by the transcription factor E2F4. The goal of our on-going research is to define and characterize the transcriptional complexes resident on the FGFR1 regulatory regions as well as those interactions off the promoter that govern its expression in both proliferating myoblasts and differentiated muscle fibers. These studies provide insight into mechanisms that regulate not only muscle cell proliferation and differentiation, but regulation of cell proliferation in general.
Transcriptional Regulation of Cardiomyocyte Proliferation
DiMario JX. (2018) KLF10 Gene Expression Modulates Fibrosis in Dystrophic Skeletal Muscle. Am J Pathol. 188:1263-1275.
Hatch K, Pabon A, DiMario JX. (2017) EMX2 activates slow myosin heavy chain 2 gene expression in embryonic muscle fibers. Mech Dev. 147:8-16.
Cavanaugh E, DiMario JX. (2017) Sp3 controls fibroblast growth factor receptor 4 gene activity during myogenic differentiation. Gene. 617:24-31.
Cavanaugh EJ, DiMario JX. (2016) C/EBPÎ± represses slow myosin heavy chain 2 gene expression in developing avian myotubes. Biochim Biophys Acta. 1860(11 Pt A):2355-2362.
Weimer K, DiMario JX. (2015) Muscle fiber type specific activation of the slow myosin heavy chain 2 promoter by a non-canonical E-box. Biochem Biophys Res Commun. 469:842-847.
Weimer K, Theobald J, Campbell KS, Esser KA, DiMario JX. (2013) Genome-wide expression analysis and EMX2 gene expression in embryonic myoblasts committed to diverse skeletal muscle fiber type fates. Dev Dyn. 242:1001-1020.
Parakati R, DiMario JX. (2013) Repression of myoblast proliferation and fibroblast growth factor receptor 1 promoter activity by KLF10 protein. J Biol Chem. 288:13876-13884.
Oh HJ, Abraham LS, van Hengel J, Stove C, Proszynski TJ, Gevaert K, DiMario JX, Sanes JR, van Roy F, Kim H. (2012) Interaction of Î±-catulin with dystrobrevin contributes to integrity of dystrophin complex in muscle. J Biol Chem. 287:21717-21728.
Theobald J, DiMario JX. (2011) Lineage-based primary muscle fiber type diversification independent of MEF2 and NFAT in chick embryos. J Muscle Res Cell Motil. 31:369-381.
Mitchell DL, DiMario JX. (2010) Bimodal, reciprocal regulation of fibroblast growth factor receptor 1 promoter activity by BTEB1/KLF9 during myogenesis. Mol Biol Cell. 21:2780-2787.
Crew JR, Falzari K, DiMario JX. (2010) Muscle fiber type specific induction of slow myosin heavy chain 2 gene expression by electrical stimulation. Exp Cell Res. 316:1039-1049.
Mitchell DL, DiMario JX. (2009) AP-2 alpha suppresses skeletal myoblast proliferation and represses fibroblast growth factor receptor 1 promoter activity. Exp Cell Res. 316:194-202.
Seyed M and DiMario JX. (2008) Fibroblast Growth Factor Receptor 1 Gene Expression Is Required for Cardiomyocyte Proliferation and Is Repressed by Sp3. J. Mol. Cell. Cardiol. 44:510-519.
Seyed M and DiMario JX (2007) Sp1 Is Required for Transcriptional Activation of the Fibroblast Growth Factor Receptor 1 Gene in Neonatal Cardiomyocytes. Gene 400:150-157.
Graduate and Postdoctoral Training
Within the School of Graduate and Postdoctoral Studies at Rosalind Franklin University of Medicine and Science, the laboratory offers training opportunities for graduate student and postdoctoral fellows. Graduate students may matriculate into degree programs that confer MS, PhD, or combined MD/PhD degrees.
Postdoctoral fellows have the opportunity to investigate numerous aspects of the cellular and molecular mechanisms of skeletal and cardiac muscle development. Postdoctoral fellows are encouraged to develop new lines of research, apply for extramural support, and gain experience in research, laboratory management, and grant writing. Those interested in postdoctoral training opportunities should contact Dr. Joseph DiMario directly at firstname.lastname@example.org.