February 2002

From Journal of Clinical Investigation

A new route to branching morphogenesis

Branching morphogenesis, one of the unifying themes in organogenesis, allows a cluster of epithelial cells to generate a system of branching tubules and ducts, rather than a simple, flat sheet. This event can be recapitulated in 3-dimensional culture systems, when spontaneously formed kidney, lung, or mammary cell aggregates are treated with HGF or any of several other agents. Following up on a recent report that overexpression of the renal epithelial cell membrane protein polycystin-1 stimulates branching of these cells in culture, Nickel and coworkers have now worked out some of the molecular interactions that distinguish this response from the better known pathway induced by HGF. Mutations in the human polycystin-1, or in the interacting protein polycystin-2, are the most frequent cause of polycystic kidney disease, indicating that these two proteins are required for normal kidney cell proliferation and for the structure and function of the renal epithelium. Overexpression of polycystin-1 ? or, as the authors now show, of the protein?s polycystin-2?interacting region ? leads to greater cell motility, stimulates cell elongation and branching, and causes rounded clusters of murine inner medullary connecting duct epithelial cells to generate tubules in culture. Unlike HGF-stimulated morphogenesis, which is mediated by the Ras signaling pathway, these responses depend on activation of protein kinase C-a. Nickel et al. find that the two pathways can operate in parallel, since HGF enhances this morphological change even in the polycystin-overexpressing cell.











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