Mammalian kidney emerges from metanephric mesenchyme following the insertion of a migrating ureteric bud. The pattern morphology of mesenchymal speation during tubular segmentation s remarkably complex, and the relative contribution ofpattern gradients from the microenvironment versus the instructive role of Individual cells is not known. We have started to exami the differentiation of metanephrlc mesenchyme using cultures of metanephric ridge (MMR) cells from day 13.5 mouse embryos to investigate the conversion of mesenchyme toward kidney epithelium in vitro. One of our mesenchymal clones, MMR1, expresses little Pax2, uvomorulin, or cytokeratin but does express neural cell adhesion molecule, bcl2, and desmin; these are properties c ent with an early stem cell. Coculture of MMR1 cells with embryonic spinal cord leads to the induction of a more differentiated cell phenotype characterized by decreased expresson of neural cell adhesion molecule, the appearance of uvomorulin, and the emergence of cytokeratin, all consistent with an evolution toward epithelium. We were also able to detect the hepatocyte growth factor receptor c-met on MMR1 cells by indt Immuwnofuorescence. When MMR1 cells were stimuinted with hepatocyte growth factor, neural cell adhesion molecule expresion decreased and uvomorulin appeared. This effect of hepatocyte growth factor, as a single cytokine, may be important in the early assemblage of kidney, since we were able to detect mRNA tnscrip enIng c-met from mouse embryo metanephric kidneys.The metanephric kidney emerges from condensing mesenchyme as organized tubules lined by renal epithelium differentiating toward maturity. The ureteric bud, an epithelial outgrowth of the Wolffian duct, contacts and transforms this metanephros along pathways of epithelial divergence and specialization starting as early as embryonic day 11.5 (Ei1.5) in the mouse (1-3). Loose metanephric mesenchyme first condenses around the ureteric bud; comma-shaped bodies then form and elongate into S-shaped bodies. Tubules become segmented over the next 1-2 days, and one pole of the S-shaped body is vascularized by invading endothelial cells to form a glomerulus (4). Nephron segmentation by progenitor cells probably occurs in some kind of ordered cascade (5). During this process of induction, the early-stage neural cell adhesion molecule (NCAM) disappears (6), and the production of collagen types I and III decreases, while new collagen type IV emerges as part of the tubular basement membrane (7). Epithelial cell proteins including uvomorulin (Ecadherin), laminin A chain (8), and cytokeratin also become evident (9), and apoptosis thins unwanted anlage from the organizing parenchymal mass (10). Attempts to study this process in vitro have met with some limited success, and although the metanephros in organ culture can be induced to form tubules using embryonic spinal cord separated by filters (11, 12), similar events have not been reported from work in single origin cell cultures.The specific transducing agents that ...