Title: The role of hemojuvelin in systematic iron homeostatis
Description: My dissertation work focused on the study of the regulation of systemic iron homeostasis. I investigated iron homeostasis by working on hemojuvelin ( HJV ), a gene that is mutated in patients with severe iron overload. I identified a novel mutation in a human patient and undertook a genetic approach to study the function of hemojuvelin by making a mouse knockout of the murine ortholog of HJV. Hjv-/- mice have severe iron overload, depressed hepatic hepcidin mRNA levels, and increased expression of ferroportin protein in intestinal enterocytes and tissue macrophages. Hjv-/- mice do not mount a hypoferremic response when challenged with an inflammatory stimulus. Restoration of hepcidin expression by breeding Hjv-/- mice to transgenic hepcidin mice restores iron balance to the Hjv-/- mice. This dissertation describes the identification and characterization of HJV as a bone morphogenetic protein (BMP) co-receptor and proposes that HJV regulates hepcidin expression through the BMP signaling pathway. HJV upregulates hepcidin expression while loss of FIN results in diminished hepcidin expression. BMP upregulates hepcidin expression in hepatocytes, but this process is blunted in Hjv-/- hepatocytes. Furthermore, biochemical studies indicated that HJV interacts with transferrin receptor 2 (TFR2) and HFE in a protein complex. Overexpression of TFR2 prevents the release of soluble hemojuvelin, an inhibitor of hepcidin expression. In summary, the work described here in this dissertation serves as the basis for future studies of the molecular control of systemic iron homeostasis.