BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression.
Impaired regulation of hepcidin expression in response to iron loading appears to be the pathogenic mechanism for hereditary hemochromatosis. Iron normally induces expression of the BMP6 ligand, which, in turn, activates the BMP/Smad signaling cascade directing hepcidin expression. The molecular function of the HFE protein, involved in the most common form of hereditary hemochromatosis, is still unknown. We have used Hfe-deficient mice of different genetic backgrounds to test whether HFE has a role in the signaling cascade induced by BMP6. At 7 weeks of age, these mice have accumulated iron in their liver and have increased Bmp6 mRNA and protein. However, in contrast to mice with secondary iron overload, levels of phosphorylated Smads 1/5/8 and of Id1 mRNA, both indicators of BMP signaling, are not significantly higher in the liver of these mice than in wild-type livers. As a consequence, hepcidin mRNA levels in Hfe-deficient mice are similar or marginally reduced, compared with 7-week-old wild-type mice. The inappropriately low levels of Id1 and hepcidin mRNA observed at weaning further suggest that Hfe deficiency triggers iron overload by impairing hepatic Bmp/Smad signaling. HFE therefore appears to facilitate signal transduction induced by the BMP6 ligand.
Kautz
Léon
L
Inserm, Toulouse, France.
Meynard
Delphine
D
Besson-Fournier
Céline
C
Darnaud
Valérie
V
Al Saati
Talal
T
Coppin
Hélène
H
Roth
Marie-Paule
MP
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism*; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D007124:Immunoenzyme Techniques; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000008:administration & dosage; D019190:Iron Overload; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism*; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism*; D051904:Smad8 Protein / Q000235:genetics / Q000378:metabolism*
D023181:Antimicrobial Cationic Peptides; C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D008565:Membrane Proteins; D012333:RNA, Messenger; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D051904:Smad8 Protein; C491621:Smad9 protein, mouse; D007501:Iron