Fred Hutchinson Cancer Research Center
1100 Fairview Avenue North
P.O. Box 19024
Seattle, WA 98109-1024
Phone: (206) 667-6825
FAX: (206) 667-6522
Research in this laboratory is centered on the genetic analysis of mouse development, with a particular emphasis on genes implicated in growth fact signaling pathways. Using gene targeting in embryonic stem (ES) cells, we have shown that platelet derived growth factor (PDGF) signaling is critical for normal development of the vasculature, cranial and cardiac neural crest cells, the somites, and oligodendrocytes. We have studied the role of fibroblast growth factor (FGF) signaling in mesodermal and neural development, and are focusing on the role of this pathway in stem cell development in the early embryo. We are also developing mice carrying small mutations that prevent various effectors from docking to the receptors, to unravel the role of various signal transduction pathways in a physiological context. Last, we are creating activating mutations in PDGF receptors to provide information on the role of this signaling pathway in the control of normal cell proliferation and cancer.
To identify downstream targets of growth factor signaling and their physiological role, we are using gene trap mutagenesis in ES cells. In this approach, a promoterless reporter gene (for instance encoding ß galactosidase) is introduced in ES cells. Expression of the reporter gene only occurs if it has disrupted an endogenous locus, typically leading to a null allele. Using a platform in which gene trap mutagenesis is coupled to DNA microarrays, we have identified and mutated numerous genes whose expression is regulated by PDGF. We are also performing gain of function screens on sensitized backgrounds to identify new signal transduction pathways that control neural crest cell behavior.
We are studying the involvement of other signaling pathways, in particular ephrin signaling, that regulate neural crest cell development. Eph receptors and ephrins function as an unusual receptor/ligand pair that can activate both forward signaling to Eph receptors as well as reverse signaling through the ephrin GPI-anchor or cytoplasmic domain. We are studying the signaling pathways through which ephrin-B1 regulates cranial neural crest development and ephrin-B2 regulates trunk neural crest development. We have also shown that ephrin signaling can mediate boundary formation during development by regulating gap junction communication.