Research Interests
My laboratory studies Kit ligand (Kitl, also called stem cell factor, mast cell growth factor and Steel factor), which is the ligand for a receptor tyrosine kinase called Kit. Both Kitl and Kit are highly conserved in mammals and together make up an intercellular signaling pathway that is required for the development of germ cells, erythroid cells, mast cells and melanocytes. In the mouse, Kitl is encoded by the Steel (Sl) locus, a locus that was first identified through classical genetic techniques. We have a large allelic series of Kitl^Sl mutants with a wide range of molecular defects and will use these mutants to further dissect Kitl function. The molecular defects in the Kitl^Sl allelic series include mutants that lack entire domains of Kitl, mutants that have missense substitutions in Kitl, and mutants that have defects in Kitl mRNA expression. Our analyses of viability and peripheral blood cells of Kitl^Sl mutant mice have revealed that several of these mutations are hypomorphic while others are null. We are performing detailed analyses of germ cell development in mice carrying hypomorphic Kitl^Sl mutations to gain further information on the functions of Kitl during germ cell development. While it is well established that Kitl mediates survival and proliferation of primordial germ cells and spermatogonia, the hypomorphic Kitl^Sl mutants may be useful for examining a role for Kitl in migration and differentiation, respectively, of these cells. In addition to these in vivo studies, we are using an in vitro system to examine the mechanism of altered function of Kitl mutants. Our results to date indicate that many of the Kitl^Sl mutant proteins are defective for intracellular processing and have reduced cell surface expression. Future studies will examine further these intracellular processing defects, as well as determinations of the levels of binding and activation of Kit by Kitl mutants, and in vitro bioactivity of Kitl mutants. To gain insight into possible structural defects in the Kitl mutants, we are using comparative molecular modeling. Last, we are taking a genetic approach to identify other gene products that affect the Kitl signaling pathway. We have evidence for a genetic modifier of the Kitl^Sl mutant phenotype and experiments are in progress to map the modifier gene.