A central task in developmental biology is the elucidation of the mechanisms through which a radially symmetric egg becomes a patterned adult. We are interested in the endogenous signals and signaling pathways that control cell fate. That is, we are trying to uncover the molecular mechanisms that tell a cell whether to become for example, a brain cell, a fat cell, or a disease cell. During embryogenesis, the signaling pathways are normal, while in the disease states, the pathways are abnormal. We study both development and animal models of disease with the idea that the two systems will be synergistic. We primarily study these processes by exploiting the unique advantages provided by in vivo analyses in four model organisms: C. elegans (worms), Drosophila (flies), Xenopus laevis (frogs), and mice.
A major focus of the lab is to identify and then characterize new molecules that control developmental fates. Much of our invertebrate efforts are directed towards gene discovery through genetic screens. In addition, we have developed a series of unique techniques to identify vertebrae genes. These new methodologies include a novel functional expression cloning screen, post-genomics approaches, as well as our recently discovered method to identify cell-surface and secreted molecules. To extend our studies from development to models of disease, we disrupt the developmentally important molecules through homologous recombination in the mouse. For example, we studied Smad genes because of their importance during embryogenesis. In addition, Smads are mutated in many human cancers including colon cancer, which affects 5% of Americans. To develop an animal model of colon cancer we generated Smad knockout mice. We found that 100% of Smad3 mutant mice develop metastatic colon cancer that in many important ways mimics the human disease. These studies provide a paradigm for the direction of our research efforts.
RECENT PUBLICATIONS
Graff JM, "Embryonic Patterning : To BMP or not to BMP, that is the question" Cell, 89:171-174, 1997
LeSueur JA, Fortuno III ES, McKay RM, and Graff JM, "Smad10 is required for formation of the frog nervous system" Developmental Cell, 2:771-783, 2002
McKay RM, McKay JP, Avery L, and Graff JM, "C. elegans: a model for exploring the genetics of fat storage." Developmental Cell, 4:131-142, 2003
Peters JM, McKay RM, McKay JP, and Graff JM, "Casein Kinase I transduces Wnt signals" Nature, 401:345-350, 1999
Zhu, Y, Richardson, JA, Parada, LF, and Graff, JM, "Smad3 mutant mice develop metastatic colorectal cancer" Cell, 94:703-714, 1998
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