Runt domain (Runx) transcription factors are key regulators of animal development. Each of the three mammalian Runx genes is required for the development of a major organ system, and in humans all three are associated with disease caused by uncontrolled cell proliferation. RUNXl is required for definitive hematopoiesis, and is the most frequently mutated gene in human leukemia; RUNX2 is required for osteogenesis, and its haploinsufficiency causes cleidocranial dysplasia; and RUNX3 is required for neural development in the dorsal root ganglia and for control of cell proliferation in the developing stomach, and is frequently deleted or silenced in human stomach cancer. The purpose of this grant is to define the molecular mechanisms through which Runx proteins control cell proliferation during development. Toward this end we are using sea urchin embryogenesis as a simplified model system. Unlike mammals, which have 3 Runx genes, the sea urchin Strongylocentrotus purpuratus has only a single Runx gene (SpRunt). As is the case with other Runx proteins, SpRunt forms a heterodimer with a beta subunit (SpCBFbeta). Our preliminary data show that SpRunt is required for the normal program of cell proliferation during embryogenesis and for the transcriptional activation of cyclin D.
The specific aims of this grant are: (1) to further define the roles of SpRunt in cell proliferation; (2) to determine how SpRunt functions within the context of the cyclinD cis-regulatory system; and (3) to investigate how SpRunt activity is developmentally regulated by its heterodimeric partner, SpCBFbeta.
These aims will be achieved by exploiting the strengths of the sea urchin embryo as a system for biochemical and molecular analyses of cell physiology, gene regulation, and development, and the availability of the S. purpuratus genome sequence, which will greatly facilitate both the cis-regulatory analysis of genes and the identification of purified proteins by mass spectrometry.
| Rizzo, Francesca; Coffman, James A; Arnone, Maria Ina (2016) An Elk transcription factor is required for Runx-dependent survival signaling in the sea urchin embryo. Dev Biol 416:173-186 |
| McCarty, Christopher M; Coffman, James A (2013) Developmental cis-regulatory analysis of the cyclin D gene in the sea urchin Strongylocentrotus purpuratus. Biochem Biophys Res Commun 440:413-8 |
| Robertson, Anthony J; Coluccio, Alison; Jensen, Sarah et al. (2013) Sea urchin akt activity is Runx-dependent and required for post-cleavage stage cell division. Biol Open 2:472-8 |
| Coffman, James A (2009) Is Runx a linchpin for developmental signaling in metazoans? J Cell Biochem 107:194-202 |
| Robertson, Anthony J; Coluccio, Alison; Knowlton, Peter et al. (2008) Runx expression is mitogenic and mutually linked to Wnt activity in blastula-stage sea urchin embryos. PLoS One 3:e3770 |
| Coffman, James A; Denegre, James M (2007) Mitochondria, redox signaling and axis specification in metazoan embryos. Dev Biol 308:266-80 |
| Robertson, Anthony J; Croce, Jenifer; Carbonneau, Seth et al. (2006) The genomic underpinnings of apoptosis in Strongylocentrotus purpuratus. Dev Biol 300:321-34 |
| Sea Urchin Genome Sequencing Consortium; Sodergren, Erica; Weinstock, George M et al. (2006) The genome of the sea urchin Strongylocentrotus purpuratus. Science 314:941-52 |
| Robertson, Anthony J; Dickey-Sims, Carrie; Ransick, Andrew et al. (2006) CBFbeta is a facultative Runx partner in the sea urchin embryo. BMC Biol 4:4 |
| Fernandez-Guerra, Antonio; Aze, Antoine; Morales, Julia et al. (2006) The genomic repertoire for cell cycle control and DNA metabolism in S. purpuratus. Dev Biol 300:238-51 |
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