Kidney organogenesis results from an interaction of ureteric bud and metanephric mesenchyme. In the presence of the ureteric bud, mesenchymal cells expand and then convert to epithelia and form nephrons; in the absence of the ureteric bud these cells die by apoptosis. Hence, the ureteric bud has been called the inducer of the nephron, but neither its signals nor their cellular targets in the mesenchyme have been known. Further, an unequivocal identification and isolation of an epithelial progenitor is lacking. My long-term goal is to discover the mechanisms that produce nephrons from mesenchymal cells. To do this, I decided to identify ureteric bud factors that regulate the mesenchyme. I produced cell lines from the ureteric bud, and by using freshly isolated mesenchyme to screen proteins, I purified a series of factors that cause growth or cell conversion. One inducer is Leukemia Inhibitory Factor (LIF), an IL-6 type cytokine. LIF is expressed by the ureteric bud and deletion of its receptor hinders kidney development. Thus, LIF is the first authentic and necessary inducer of nephrogenesis. I now propose to identify epithelial precursors in the metanephric mesenchyme. This is possible because after the addition of LIF, nephrons appear from discrete clusters of cells that are visible by low power magnification. The cells that give rise to this phenomenon are easily isolated, permitting lineage, gene expression, and morphologic studies to confirm that they are the progenitors of the nephron. Using these isolated progenitors, we then determine if interaction with the ureteric bud is necessary and sufficient to induce their conversion, or whether other intra-mesenchymal signals are required. In fact, a protein from kidney stroma targets epithelial precursors and permits induction by LIF, and I propose to identify this factor. These proposals fractionate and then reconstitute the metanephric mesenchyme from its components to identify epithelial precursors and show that combinatorial signaling by factors from the ureteric bud and from the stroma are responsible for converting precursor cells to nephrons.
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