Neogenin inhibits HJV secretion and regulates BMP-induced hepcidin expression and iron homeostasis

Dai Hoon Lee, Li Juau Zhou, Zheng Zhou, Jiau Xiu Xie, Ji Ung Jung, Yu Liu, Cai Xia Xi, Lin Mei, Wen Cheng Xiong

Research output: Contribution to journalArticle

105 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3136-3145
Number of pages10
JournalBlood
Volume115
Issue number15
DOIs
StatePublished - Apr 15 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Lee, D. H., Zhou, L. J., Zhou, Z., Xie, J. X., Jung, J. U., Liu, Y., Xi, C. X., Mei, L., & Xiong, W. C. (2010). Neogenin inhibits HJV secretion and regulates BMP-induced hepcidin expression and iron homeostasis. Blood, 115(15), 3136-3145. https://doi.org/10.1182/blood-2009-11-251199