title: Neogenin inhibits HJV secretion and regulates BMP-induced hepcidin expression and iron homeostasis.
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.
authors.affiliation: Institute of Molecular Medicine and Genetics, and Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA.
authors.forename: Dae-Hoon
authors.initials: DH
authors.lastname: Lee
authors.forename: Dai-Hoon
authors.initials: DH
authors.lastname: Lee
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Zhou
authors.forename: Li-Juau
authors.initials: LJ
authors.lastname: Zhou
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhou
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Xie
authors.forename: Jiau-Xiu
authors.initials: JX
authors.lastname: Xie
authors.forename: Ji-Ung
authors.initials: JU
authors.lastname: Jung
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Cai-Xia
authors.initials: CX
authors.lastname: Xi
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Xiong
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D000071020:Hemochromatosis Protein; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D064451:Hepcidins; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000235:genetics / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D023181:Antimicrobial Cationic Peptides; D055396:Bone Morphogenetic Protein 2; D027682:Cation Transport Proteins; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C504414:HJV protein, mouse; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D008565:Membrane Proteins; D051785:Smad Proteins; D000098742:Ferroportin; C091279:neogenin; D007501:Iron