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Hans-Georg Simon, PhDAssociate Professor
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My laboratory is interested in the formation of pattern or in other words, the emergence of biological organization. For our studies we are using the developing vertebrate limb and more recently the heart. Our goal is to understand on a molecular level how organ specification in vertebrate embryogenesis is controlled, and how problems during development predispose an organism for disease. We are addressing these questions by employing three different experimental animal models: 1) the chick, which allows manipulations of the embryo in ovo; 2) the zebrafish, which, because of rapid reproduction time, small and transparent embryos facilitates studies on the genetic, cell, and molecular level, and 3) the mouse, because of superior technologies available for genetic manipulation. The maintenance and potential repair of tissues as adults is another biological problem of very practical importance in regenerative medicine. Employing urodele amphibians like the newt, we are studying nature’s solution to the problem. Newts, in contrast to higher vertebrates, can replace lost limbs and portions of the heart throughout their lifetime. In comparing development and regeneration we want to learn how specific patterns are established during embryogenesis, but also how certain animal species manage to re-build lost structures as adults.
As candidates for “limb-identity” genes we have isolated genes with a forelimb (arm) and hindlimb (leg)-specific expression profile. These isolates belong to a family of evolutionary conserved, so called T-box transcription factors. The forelimb-specific (Tbx5) and the hindlimb-specific (Tbx4) genes are currently the main focus of our work. Direct evidence for a role in controlling limb pattern comes from mutations in Tbx5 in humans, which cause Holt-Oram syndrome, a disease characterized by birth defects of the upper limbs and heart septation. In contrast, mutations in Tbx4 result in a disorder called small patella syndrome with skeletal defects of the patella, pelvis, and feet. In a molecular screen we have identified proteins that physically interact with Tbx5. Interestingly, one of these proteins, Pdlim7 (LMP4), demonstrated a tight co-expression with Tbx4 or Tbx5 in the developing limbs and the heart. Our molecular, biochemical, and cell biology work revealed that Pdlim7 links the Tbx4/5 transcription factors to intracellular signaling pathways. The discovery of Tbx protein-protein interactions is a first inroad towards the understanding of Tbx transcription factor regulatory networks, and it provides new insights into common pathways that are active in the limbs and heart.
The laboratory is using a range of molecular techniques to clone and engineer genes, retroviral gene transfer, antisense gene knock-down, and genetic knockout techniques for functionally testing them in vivo; biochemical techniques to determine the encoded protein structure and function, and cell biological techniques to visualize subcellular localizations of mRNA and protein.
Khan, P., Linkhart B., Simon H.-G. Different regulation of T-box genes Tbx4 and Tbx5 during limb development and limb regeneration. Dev Biol 250, 383-392 (2002).
Stock , S.R., Blackburn, D., Gradassi, M., Simon, H.-G. Bone formation during forelimb regeneration: a microtomography (MicroCT) analysis. Dev Dynamics 226, 410-417 (2003).
Imokawa, Y., Gates, P.B., Chang, Y.-T., Simon, H.-G., Brockes, J.P. Distinctive expression of Myf5 in relation to differentiation and plasticity of newt muscle cells. Int. J. of Dev. Biol. 48, 285-291 (2004).
Krause, A., Zacharias, W., Linkhart, B., Camarata, T., Law, E., Lischke, A., Miljan, E., Simon, H.-G. Tbx5 and Tbx4 Transcription factors interact with a new chicken PDZ-LIM protein in limb and heart development. Dev. Biol. 273, 106-120 (2004).
Isphording, D., Leylek, A.L., Yeung, J., Mischel, A., and Simon, H.-G. T-box genes and congenital heart/limb malformations. Clin. Genet. 66, 253-264 (2004).
Camarata, T., Bimber, B., Kulisz, A., Chew, T.L., Yeung, J., Simon, H.-G. LMP4 regulates Tbx5 protein sub-cellular localization and activity. J. Cell Biol. 174, 339-348 (2006).
Bimber, B., Dettman, R., Simon, H.-G. Differential regulation of Tbx5 protein expression and subcellular localization during heart development. Dev. Biol. 302, 230-242 (2007).
Kulisz, A. and Simon, H.-G. An Evolutionarily conserved nuclear export signal facilitates cytoplasmic localization of the Tbx5 transcription factor. Mol. Cell. Biol. 28, 1553-1564 (2008).
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View Publications by Hans-Georg Simon listed in the National Library of Medicine (PubMed). |
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