Roles of HGF and its family molecules in development.

肝细胞生长因子(HGF)最初被认为是一种强大的肝细胞有丝分裂原，是一种间质来源的因子，能在多种细胞中诱导有丝分裂、运动和形态发生反应。HGF的一个特异性受体是c-Met跨膜异二聚体酪氨酸激酶。在本项目中，我们研究了HGF在胚胎发生和器官发生中的作用。我们克隆了非洲爪哇HGF和c-Met/HGF受体的cDNA，采用显性-负性策略分析了HGF和c-Met之间的功能偶联。酪氨酸激酶负性蛋氨酸在非洲爪哇胚胎中的显性表达导致肝脏、肠道和肾脏等内脏器官发育严重缺陷。在大鼠胚胎发育和器官发生过程中，HGF在间充质组织中表达，而c-met在上皮和某些间充质细胞中表达。在肺发育过程中，HGF mRNA定位于间充质组织，而c-met mRNA定位于发育中的肺上皮细胞。利用抗体和反义寡核苷酸…此外，在肺原基器官培养中，我们发现发育中的肺上皮细胞的分支形态发生通过两条不同的途径来调节：KGF受体途径和c-Met/HGF受体途径。同样，在牙齿发育过程中，HGF mRNA定位于发育中的牙间充质，分化为成牙本质细胞，而c-met mRNA定位于釉质上皮组织。当牙胚在正义或反义HGF寡核苷酸存在时，牙胚的形态发生被反义HGF寡核苷酸破坏，表明HGF和c-Met之间的功能偶联调控着牙齿发育过程中的整体形态发生过程。此外，我们还发现HGF可以诱导乳腺上皮细胞系中的分支管发生，并且分枝形态发生的诱导主要是HGF所特有的。HGF是一种高度保守的分子，在从两栖动物到哺乳动物的器官发生过程中，作为间充质来源的媒介参与了形态发生上皮-间充质的相互作用。较少

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 … More 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