Professor of Biochemistry
Adjunct Professor of Biology
BS 1979, Stanford University
PhD 1985, Harvard University
Regulation of Embryonic Patterning in Zebrafish
||The vertebrate body grows from the neck down by the progressive addition of cells from a mesodermal progenitor population located at the most posterior end of the embryo. A major interest in the lab is to understand the mechanisms that regulate this process. Our focus is on the signaling factors that pattern and sustain the mesodermal progenitors, including Nodals, Wnts, Fgfs and Bmps, and their interaction with transcription factors that regulate the progenitors, particularly members of the T-box family. Recently (Szeto and Kimelman, 2006), we demonstrated that the position of the mesodermal progenitors along the body is regulated by a combination of Nodal and Bmp signals, which regulate a clock that tells the mesodermal progenitors when to commit to differentiation. Our current research involves the production of transgenic zebrafish that will allow us to understand how the fate and proliferation of the mesodermal progenitors is regulated.
Regulation of morphogenesis in Zebrafish
||During gastrulation, the vertebrate embryo undergoes dramatic morphological changes to form the final body plan. One of these morphological transformations involves a process called convergence & extension, which moves the mesodermal cells into their final position in the embryo. We recently (Weiser et al., 2007) found that a scaffolding protein called Gravin regulates a major change in the cells from convergence (migratory behavior) to extension (intercalative behavior). When the cells lack Gravin, they fail to suppress a particular type of protrusive activity called blebbing, which is important for cell migration; it is this failure to shut down blebbing in the absence of Gravin that prevents embryo extension, resulting in a deformed body. These results have interesting implications not only for development, but also for metastasis since Gravin is implicated as a tumor suppressor. We are currently working to understand how Gravin is regulated, and to identify the mechanism by which Gravin suppresses blebbing in the early embryo.
Structural Analysis of the Wnt Signaling Pathway
||Together with Wenqing Xu (Biostructure Department), we have been taking a structural approach to understanding the Wnt signaling pathway, which plays major roles in embryonic development, stem cell maintenance and disease. We use X-ray crystallography to examine the interactions between different proteins in this pathway, and then follow up these studies with various biochemical and embryological analyses. From these studies we have developed a model for the regulation of the key mediator of this pathway, β-catenin, by a complex of proteins known as the Destruction Complex. We are continuing our analysis of this pathway.
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