Identification of pleiotrophin as a mesenchymal factor involved in ureteric bud branching morphogenesis

Branching morphogenesis is central to epithelial organogenesis. In the deve loping kidney, the epithelial ureteric bud invades the metanephric mesenchy me, which directs the ureteric bud to undergo repeated branching. A soluble factor(s) in the conditioned medium of a metanephric mesenchyme cell line is essential for multiple branching morphogenesis of the isolated ureteric bud. The identity of this factor had proved elusive, but it appeared distin ct from factors such as HGF and EGF receptor ligands that have been previou sly implicated in branching morphogenesis of mature epithelial cell lines. Using sequential column chromatography, we have now purified to apparent ho mogeneity an 18 kDa protein, pleiotrophin, from the conditioned medium of a metanephric mesenchyme cell line that induces isolated ureteric bud branch ing morphogenesis in the presence of glial cell-derived neurotrophic factor . Pleiotrophin alone was also found to induce the formation of branching tu bules in an immortalized ureteric bud cell line cultured three-dimensionall y in an extracellular matrix gel. Consistent with an important role in uret eric bud morphogenesis during kidney development, pleiotrophin was found to localize to the basement membrane of the developing ureteric bud in the em bryonic kidney. We suggest that pleiotrophin could act as a key mesenchymal ly derived factor regulating branching morphogenesis of the ureteric bud an d perhaps other embryonic epithelial structures.