Stem Cells to Organs with GATA Transcription Factors
Key Words: developmental biology, transcription factors, stem cells, organogenesis, signal transduction
Animal development is controlled by signaling pathways that somehow direct differentiation of a large number of specific cell lineages and the formation of many complicated organ systems. This is exemplified by the BMP signaling pathway and a small family of GATA transcription factors that together control stem and progenitor cell fate, lineage differentiation choices, and morphogenetic programs critical for cardiovascular, gastro-intestinal, and hematopoietic development. These pathways continue to be used throughout life and disruptions in the various components cause specific human diseases. Fortunately, the pathways are highly conserved throughout evolution, justifying the use of animal models to further understand specificity of gene function. We are developing novel embryonic and stem cell models to manipulate components of the BMP-GATA pathway and to define specificity for various components. Much of the work uses the zebrafish model system, which has major advantages for both embryological and genetic experiments, and is also a vertebrate with well conserved tissue and organ systems compared to humans. We also use embryonic stem cells models. A major goal of this work is to define potential targets for treating debilitating human diseases including heart disease and leukemia.
Some examples of the approaches taken by our laboratory to understand the regulation and function of GATA transcription factors includes:
- Use of antisense morpholinos to selectively target individual or combinations of GATA factors during zebrafish embryogenesis, to gain insight into the “GATA code” that regulates various aspects of blood, liver, pancreas, and heart development.
- Generation of transgenic zebrafish that express GFP or RFP under the control of GATA4 or GATA6 genomic sequences to find the cis-elements and trans-factors that target expression of these GATA factors to specific lineages and tissues.
- Development of transgenic approaches that allow us to conditionally inactivate BMP signaling.
- Generation of novel lines of murine ES cells that also allow us to manipulate BMP and GATA activity at various stages of in vitro development for studying the development of hematopoietic, cardiogenic, and other cell lineages
In summary, we develop and exploit various animal models, so that we can understand how cell types, tissues, and organs form under the control of GATA transcription factors, and why this process can fail during embryogenesis and throughout life.
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Selected References: 
Oren, T., Torregroza, I., and Evans, T. An Oct-1 binding site mediates activation of the gata2 promoter by BMP signaling. Nucl. Acids Res. 33: 4357-4367, 2005.
Holtzinger, A. and Evans, T. GATA4 regulates the formation of multiple organs. Development 132: 4005-4014, 2005.
Torregroza, I. and Evans, T. Tid-1 is a Smad-binding Protein and can modulate Smad7 dorsalizing activity in developing embryos. Biochem J. 393: 311-320, 2006.
Yergeau, D.A., Schmerer, M., Kuliyev, E., Evans, T., and Mead, P.E. Cloning and expression pattern of the Xenopus erythropoietin receptor. Gene Exp. Patterns. 6: 420-425, 2006.
Gupta, S., Zhu, H., Zon, L.I., and Evans, T. BMP Signaling Restricts Hemato-vascular Development from Lateral Mesoderm during Somitogenesis. Development. 133: 2177-2187, 2006.
Ghatpande, S., Brand, T., Zile, M., and Evans, T. Bmp2 and Gata4 function additively to rescue heart tube development in the absence of retinoids. Dev. Dyn. In Press, 2006.
Schmerer, M., Pascal, A., Torregroza, I, Umbhauer, M., and Evans, T. STAT5 acts as a repressor to regulate early embryonic erythropoiesis. Blood. In Press, 2006.
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