NEW IRON TRAFFICKING PATHWAY IN EPITHELIAL INDUCTION

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We know very little about how developing organs obtain iron, but this topic is of great importance in human gestation. Indeed, organogenesis can initiate in the absence of transferrin/transferrin receptor, and in many lineages, iron delivery by transferrin is stage specific. However, there are few, if any proteins that can substitute for, or complement transferrin. These studies are of general importance because acquisition of iron is required for growth, and it is of local importance, because iron regulates specific subsets of genes by transcriptional and translational effects. My lab is dedicated to finding mechanisms of kidney induction, a process that generates nephrons from mesenchymal cells. We previously identified a set of cytokines that stimulate this conversion and now we have identified a new nephron inducer called Ngal, a member of the lipocalin superfamily. These proteins are not well known, and functional data are limited, but they are thought to transport low molecular weight compounds, which they deliver to cells by endocytosis. We propose that Ngal can transport iron, and that its inductive activity results from iron-Ngal. Ngal was not a substitute for transferrin-they traffic to different organelles and they target different domains in the developing mesenchyme. In vitro, Ngal and transferrin were both required for induction, acting in a sequential fashion. To evaluate Ngal traffic, we will isolate the Ngal receptor. The receptor should describe a domain of cells in the periphery of the kidney that is likely to include epithelial progenitors and stroma and it will describe a unique subcellular pathway. The identification is also important in order to evaluate why Ngal is so highly expressed in a variety, of epithelial diseases. Then we will identify the pool of iron that regulates gene expression and determine how it varies with development by using a novel genetic probe in vivo. The response to this pool of iron is tested by examining candidate genes and microarrays; it appears to include genes that are known to control kidney development. Lastly, we will test the hypothesis that iron delivery is required at particular stages of mesenchymal conversion by first determining whether Ngal requires iron for its inductive activity in vitro, and then examining when and where transferrin is essential in vivo. The later requires rescue of the embryos in vivo. These studies implicate iron as a critical regulator in morphogenesis, and define its stage specific functions during the conversion of mesenchyme to epithelia.