Robert A. Welch Distinguished Chair in Science Annie and Willie Nelson Professorship in Stem Cell Research Pogue Distinguished Chair in Research on Cardiac Birth Defects
Our laboratory is interested in basic regulatory mechanisms in developmental biology. We work primarily with muscle cells as a model system to investigate two major questions. (1) How do multipotential embryonic stem cells become committed to specific fates that result in activation of unique sets of cell type specific genes? (2) How do the signal transduction pathways regulating cell proliferation interface with the mechanisms for cell differentiation?
There are three major muscle cell types, skeletal, cardiac, and smooth, which express many of the same muscle specific genes, but which are phenotypically distinct. We have cloned several important transcription factors that act at different steps in the developmental pathways leading to the formation of these different muscle cell types. Among these is a family skeletal muscle specific basic helix loop helix (bHLH) transcription factors that can activate the complete program for skeletal muscle differentiation when expressed ectopically in a variety of muscle cell types. Gene knockout experiments in transgenic mice have demonstrated that these bHLH factors act within a genetic pathway to establish skeletal myoblast identity and to activate muscle structural genes during differentiation. We are using a variety of approaches to define the mechanisms by which these factors activate the skeletal muscle differentiation program and to identify regulatory proteins with which they interact. These myogenic bHLH transcription factors are also targets for several signal transduction cascades that induce and repress muscle differentiation. We are investigating the role of regulated phosphorylation of the myogenic bHLH factors in the control of their transcriptional activity and how these factors may interface with the cell cycle machinery.
We are also studying the mechanisms that control formation of the heart and vasculature during embryogenesis. We have identified a new subclass of bHLH transcription factors that is expressed in precursors of the heart and is required for looping of the early embryonic heart tube. By identifying the target genes for these factors and by determining how these regulators are themselves regulated, we hope to eventually understand the complex morphogenetic pathways leading to heart formation.
Recent studies have shown that the basic genetic pathways that control muscle development are conserved from Drosophila to humans. We have exploited this cross species conservation to rapidly dissect the genetic hierarchies controlling muscle development using Drosophila as a model system. Genes that are shown to regulate muscle development in Drosophila can subsequently be tested for their functions during mouse embryogenesis using gain and loss of function approaches.
RESEARCH INTERESTS
Muscle Development
Transcriptional Regulation
RECENT PUBLICATIONS
Arnold, M.A., Kim, Y., Czubryt, M.P., Phan, D., McAnally, J., Qi, X., Shelton, J.M., Richardson, J.A., Bassel-Duby, R., and Olson, E.N., "The MEF2C transcription factor controls chondrocyte hypertrophy and bone development" Dev. Cell, 12:377-389, 2007
Song, K., Backs, J., McAnally, J., Qi, S., Gerard, R.D., Richardson, J.A., Hill, J.A., Bassel-Duby, R., and Olson, E.N., "The transcriptional coactivator CAMTA2 stimulates cardiac growth by opposing class II histone deacetylases" Cell, 125:453-466, 2006
Chang, S., Young, B., Li, S., Qi, S., Richardson, J.A., and Olson, E.N, "Histone deacetylase 7 maintains embryonic vascular integrity by repression of MEF2-dependent MMP10 expression" Cell, 126:321-334, 2006
Garry, D.J., and Olson, E.N, "A common progenitor at the heart of development" Cell, 127:1101-1104, 2006
Creemers, E.E., Sutherland, L.B., Oh, J., Barbosa, A.C., and Olson, E.N., "Coactivation of MEF2 by the SAP domain proteins Myocardin and MASTR" Molecular Cell, 23:83-96, 2006
SIGNIFICANT PUBLICATIONS
Vega, R. B., Matsuda, K., Oh, J., Barbosa, A., Yang, X, Meadows, E., McAnally, J., Pomajzl, C., Shelton, J. M., Richardson, J. A., Karsenty, G., and Olson, E. N., "Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis" Cell, 119:555-566, 2004
Van Rooij, E., Sutherland, L.B., Qi, X., Richardson, J. A., Hill, J., and Olson, E. N., "Control of stress-dependent cardiac growth and gene expression by a microRNA" Science, 316:575-579, 2007
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