No abstract

Neogenin, a deleted in colorectal cancer (DCC) family member, has been identified as a receptor for the neuronal axon guidance cues netrins and repulsive guidance molecules repulsive guidance molecules (RGM). RGMc, also called hemojuvelin (HJV), is essential for iron homeostasis. Here we provide evidence that neogenin plays a critical role in iron homeostasis by regulation of HJV secretion and bone morphogenetic protein (BMP) signaling.Livers of neogenin mutant mice exhibit iron overload, low levels of hepcidin, and reduced BMP signaling. Mutant hepatocytes in vitro show impaired BMP2 induction of Smad1/5/8 phosphorylation and hepcidin expression. Neogenin is expressed in liver cells in a reciprocal pattern to that of hepcidin, suggesting that neogenin functions in a cell nonautonomous manner. Further studies demonstrate that neogenin may stabilize HJV, a glycosylphosphatidylinositol-anchored protein that interacts with neogenin and suppresses its secretion. Taken together, our results lead the hypothesis that neogenin regulates iron homeostasis via inhibiting secretion of HJV, an inhibitor of BMP signaling, to enhance BMP signaling and hepcidin expression. These results reveal a novel mechanism underlying neogenin regulation of HJV-BMP signaling. IntroductionIron, a component of many metalloproteins, plays a crucial role in various physiologic processes, such as oxygen sensing and transport, mitochondrial electron transfer in the respiratory chain, and catalytic activity of diverse enzymes. Dysregulation of iron homeostasis leads to either iron deficiency, such as anemia, or iron overload characteristic of hereditary hemochromatosis, a relatively common inherited disorder associated with progressive organ dysfunction. 1 Cellular iron overload is toxic and causes cell death, at least in part due to free radical formation and lipid peroxidation.Hemojuvelin (HJV) is a member of a family of glycosylphosphatidylinositol (GPI)-linked cell surface proteins. It has an essential role in iron homeostasis. 2 HJV contains a putative N-terminal signal peptide, a tri-amino acid motif (the RGD site), a partial von Willebrand factor type D domain, and a C-terminal GPI anchor consensus sequence. 2,3 It is predominately expressed in the skeletal muscle, heart, and liver. 3,4 Mutations in the HJV gene is a leading cause of juvenile hemochromatosis, [5][6][7][8] and patients have low levels of hepcidin, 5,8 a crucial hormone secreted by the liver for iron homeostasis. HJV mutant mice exhibit reduced hepcidin expression and iron overload, 5,6 resembling patients with HJV mutations. Consistently, expression of HJV increases, while suppression of HJV decreases, hepcidin expression in cultured cells. 9 The mechanisms underlying HJV regulation of hepcidin expression and iron homeostasis are beginning to be elucidated. HJV was shown to function as a coreceptor for bone morphogenetic proteins (BMP). It binds to BMP2/4/6 and forms a complex with BMP receptors (type I and II). 10-12 HJV deficient mice/cells exhibit impaired BMP signaling ...