James K. Chen

Research/Lab website:   Personal Web site

The Chen laboratory studies the molecular events that regulate embryonic development and tumorigenesis, using synthetic chemistry, biochemistry, genetics, and embryology. Our research group is currently investigating the Hedgehog pathway, a signaling cascade that is involved in patterning of multiple tissues such as the neural tube, limbs, and somites. Aberrant Hedgehog pathway activation in children and adults is also linked to several cancers, including those of the skin, brain, and gut.

How cells respond to Hedgehog proteins is of particular interest to us, especially since there is recent evidence that Hedgehog signaling in vertebrates has mechanistically diverged from that in invertebrate organisms. Our efforts to gain molecular insights into this pathway involve several strategies. First, several chemicals that specifically perturb the Hedgehog pathway have been discovered, most notably the plant-derived alkaloid cyclopamine, which caused outbreak of cyclopia among grazing livestock in the 1950s. By determining the cellular targets of these small molecules we hope to better understand the biochemical mechanisms that control Hedgehog pathway activation. In addition, we are currently screening chemical libraries for additional Hedgehog signaling modulators with novel modes of action. Second, new putative Hedgehog signaling proteins have been discovered through mouse mutagenesis studies; however, how these proteins interact with other pathway components is not known. We are therefore interrogating the function of these genes in zebrafish, since this model vertebrate organism is compatible with genetic, biochemical, and chemical approaches. Third, we are developing screens for new Hedgehog components using cell culture models of this pathway and genomic libraries.

Our laboratory is also interested in how the Hedgehog pathway regulates tissue patterning and oncogenesis in vertebrates. Using both genetic and chemical perturbations of Hedgehog signaling, we are studying cell migration processes and tumor formation in zebrafish. These investigations have concurrently involved the development of new technologies for gene regulation in this model organism, including a chemically inducible gene expression system and reagents for conditional gene silencing. These methods will be used to evaluate the role of individual Hedgehog pathway components in embryonic development, and their generality promises to provide new research opportunities for the zebrafish community.