| Research Abstract |
Hepatocyte growth factor (HGF), originally identified as a potent mitogen for hepatocytes, is a mesenchymal-derived factor which induces mitogenic, motogenic, and morphogenic responses in a wide variety of cells. A specific receptor for HGF is c-Met heterodimeric membrane-spanning throsine kinase. In this project, we studied roles of HGF during embryogenesis and organogenesis. We cloned Xenopus HGF and c-Met/HGF receptor cDNAs analyzed the functional coupling between HGF and c-Met, using dominant-negative strategy. Dominant expression of tyrosine kinase-minus Met in Xenopus embryo resulted in severe defects in development of internal organs, including liver, gut, and kidney. During embryogenesis and organogenesis of rat, HGF was expressed in mesenchymal tissues, while c-met in epithelial and some kinds of mesenchymal cells. During lung development, HGF mRNA was localized in mesenchymal tissue, while c-met mRNA in developing lung epithelia. Using antibodies and antisence oligonucleotide
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in organ culture of lung rudiment, we revealed that branching morphogenesis of developing lung epithelia was regulated through two distinct pathways : KGF receptor pathway and c-Met/HGF receptor pathway. Likewise, during tooth development, HGF mRNA was localized in developing dental mesenchyme which differentiate into odontoblasts, while c-met mRNA in enamel epithelial tissue. When tooth germ was cultured in the presence of sence or antisence HGF oligonucleotide, morphogenesis of tooth germ was impaired by antisence HGF oligonucleotide, indicating that the functional coupling between HGF and c-Met regulates overall morphogenic processes during tooth development. In addition, we found that HGF induces branching tuburogenesis in a cell line derived from mammary gland epithelium and that the induction of branching morphogenesis was mostly epecific to HGF.In conclusion, HGF regulates branching duct formation in several types of tissues. HGF is a highly conserved molecule as a mesenchymal-derived mediator in morphogenic epithelial-mesenchymal interactions during organogenesis from amphibian to mammalian species. Less
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