Characterization of the metHGFSF receptor tyrosine kinase in cell differentiation and during mouse development

The met proto-oncogene receptor tyrosine kinase has been identified as the receptor for hepatocyte growth factor (HGF)/scatter factor (SF). HGF/SF is a multifunctional cytokine that is expressed predominantly by mesenchymal cells and stimulates mitogenesis, motogenesis, morphogenesis of a broad spectrum of epithelial and endothelial cells in culture. To elucidate the normal physiological role for the met receptor (R) in the adult mouse, I first determined the cell-type specific expression of the met R in adult mouse tissues by in situ hybridization. I have demonstrated that the met R is generally expressed in epithelial cells of many tissues, as well as in hepatocytes. This data supports a possible role for HGF/SF and the met R in epithelial cell renewal and tissue homeostasis. I also demonstrated that met R mRNA and protein, as well as its ligand were expressed at a low level in undifferentiated P19 cells. Expression was increased as those cells were induced to differentiate into neuroectodermal derivatives following treatment with retinoic acid (RA) and into mesodermal derivatives following treatment with dimethyl sulphoxide (DMSO). In cultures treated with RA and cytosine arabinoside, both met R mRNA and protein were localized specifically to non-dividing neuronal cells. Expression of the met R in undifferentiated P19 cells and differentiated derivatives supports a role of met R in the control of cell differentiation, proliferation during embryogenesis. I therefore examined the role played by met R during mouse embryogenesis using whole mount in situ hybridization. I have localized met R expression to the ventrolateral and dorsal-medial portions of the somite dermamyotome, in epithelial cells of the primitive gut and nephrogenic cords (the primitive urinary tract), in neuroepithelium of mouse embryos of 9 and 10 day gestation. Together, these data support a role for the met R in cell migration, proliferation and tubulogenesis during embryogenesis