Neogenin inhibits HJV secretion and regulates BMP-induced hepcidin expression and iron homeostasis.
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.
Lee
Dae-Hoon
DH
Institute of Molecular Medicine and Genetics, and Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA.
Lee
Dai-Hoon
DH
Zhou
Li-Juan
LJ
Zhou
Li-Juau
LJ
Zhou
Zheng
Z
Xie
Jian-Xin
JX
Xie
Jiau-Xiu
JX
Jung
Ji-Ung
JU
Liu
Yu
Y
Xi
Cai-Xia
CX
Mei
Lin
L
Xiong
Wen-Cheng
WC
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
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