Differing impact of the deletion of hemochromatosis-associated molecules HFE and transferrin receptor-2 on the iron phenotype of mice lacking bone morphogenetic protein 6 or hemojuvelin

Hepatology

Volumn 63, Issue 1, 2016, Pages 126-137

  Latour, Chloé ^a   Besson Fournier, Céline ^a   Meynard, Delphine ^a   Silvestri, Laura ^b   Gourbeyre, Ophélie ^a   Aguilar Martinez, Patricia ^a,c   Schmidt, Paul J ^d   Fleming, Mark D ^d   Roth, Marie Paule ^a   Coppin, Hélène ^a  

^a France   (France)

^b SAN RAFFAELE HOSPITAL   (Italy)

^c HÔPITAL SAINT ELOI   (France)

^d BOSTON CHILDREN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BETA 2 MICROGLOBULIN; BONE MORPHOGENETIC PROTEIN 6; HEMOJUVELIN; HEPCIDIN; HFE PROTEIN; IRON; SMAD PROTEIN; SMAD5 PROTEIN; TRANSFERRIN RECEPTOR 2; BMP6 PROTEIN, MOUSE; HFE PROTEIN, MOUSE; HFE2 PROTEIN, MOUSE; HLA ANTIGEN CLASS 1; MEMBRANE PROTEIN; TRANSFERRIN RECEPTOR; TRFR2 PROTEIN, MOUSE;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; COMPLEX FORMATION; CONTROLLED STUDY; FEMALE; GENE DELETION; GENE EXPRESSION; GENE MUTATION; GENE REPRESSION; HEART; HEMOCHROMATOSIS; HEREDITARY HEMOCHROMATOSIS; HOMEOSTASIS; IRON OVERLOAD; LIVER; MALE; MOUSE; NONHUMAN; PANCREAS; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; ANIMAL; C57BL MOUSE; COMPARATIVE STUDY; GENE EXPRESSION REGULATION; GENETICS;

ANIMALS; BONE MORPHOGENETIC PROTEIN 6; FEMALE; GENE DELETION; GENE EXPRESSION REGULATION; HEMOCHROMATOSIS; HISTOCOMPATIBILITY ANTIGENS CLASS I; IRON; MEMBRANE PROTEINS; MICE; MICE, INBRED C57BL; PHENOTYPE; RECEPTORS, TRANSFERRIN;

EID: 84952639186     PISSN: 02709139     EISSN: 15273350     Source Type: Journal    
DOI: 10.1002/hep.28254     Document Type: Article

References (46)

1. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996;13:399-408.
2. Feder JN, Tsuchihashi Z, Irrinki A, Lee VK, Mapa FA, Morikang E, et al. The hemochromatosis founder mutation in HLA-H disrupts beta2-microglobulin interaction and cell surface expression. J Biol Chem 1997;272:14025-14028.
3. Lebron JA, Bennett MJ, Vaughn DE, Chirino AJ, Snow PM, Mintier GA, et al. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell 1998;93:111-123.
4. Camaschella C, Roetto A, Cali A, De Gobbi M, Garozzo G, Carella M, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 2000;25:14-15.
5. Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dube MP, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 2004;36:77-82.
6. Roetto A, Papanikolaou G, Politou M, Alberti F, Girelli D, Christakis J, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet 2003;33:21-22.
7. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004;306:2090-2093.
8. Kautz L, Meynard D, Monnier A, Darnaud V, Bouvet R, Wang RH, et al. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood 2008;112:1503-1509.
9. Andriopoulos B, Jr., Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 2009;41:482-487.
10. Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H, Roth MP. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet 2009;41:478-481.
11. Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC. A mouse model of juvenile hemochromatosis. J Clin Invest 2005;115:2187-2191.
12. Niederkofler V, Salie R, Arber S. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J Clin Invest 2005;115:2180-2186.
13. Trinder D, Baker E. Transferrin receptor 2: a new molecule in iron metabolism. Int J Biochem Cell Biol 2003;35:292-296.
14. Goswami T, Andrews NC. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem 2006;281:28494-28498.
15. Gao J, Chen J, Kramer M, Tsukamoto H, Zhang AS, Enns CA. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab 2009;9:217-227.
16. Schmidt PJ, Toran PT, Giannetti AM, Bjorkman PJ, Andrews NC. The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab 2008;7:205-214.
17. Rishi G, Crampton EM, Wallace DF, Subramaniam VN. In situ proximity ligation assays indicate that hemochromatosis proteins Hfe and transferrin receptor 2 (Tfr2) do not interact. PLoS One 2013;8:e77267.
18. Schmidt PJ, Fleming MD. Transgenic HFE-dependent induction of hepcidin in mice does not require transferrin receptor-2. Am J Hematol 2012;87:588-595.
19. Wallace DF, Summerville L, Crampton EM, Frazer DM, Anderson GJ, Subramaniam VN. Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload. Hepatology 2009;50:1992-2000.
20. D'Alessio F, Hentze MW, Muckenthaler MU. The hemochromatosis proteins HFE, TfR2, and HJV form a membrane-associated protein complex for hepcidin regulation. J Hepatol 2012;57:1052-1060.
21. Latour C, Kautz L, Besson-Fournier C, Island ML, Canonne-Hergaux F, Loreal O, et al. Testosterone perturbs systemic iron balance through activation of epidermal growth factor receptor signaling in the liver and repression of hepcidin. Hepatology 2014;59:683-694.
22. Solloway MJ, Dudley AT, Bikoff EK, Lyons KM, Hogan BL, Robertson EJ. Mice lacking Bmp6 function. Dev Genet 1998;22:321-339.
23. Roetto A, Di Cunto F, Pellegrino RM, Hirsch E, Azzolino O, Bondi A, et al. Comparison of 3 Tfr2-deficient murine models suggests distinct functions for Tfr2-alpha and Tfr2-beta isoforms in different tissues. Blood 2010;115:3382-3389.
24. Dupic F, Fruchon S, Bensaid M, Borot N, Radosavljevic O, Loreal O, et al. Inactivation of the hemochromatosis gene differentially regulates duodenal expression of iron-related mRNAs between mouse strains. Gastroenterology 2002;122:745-751.
25. Gutschow P, Schmidt PJ, Han H, Ostland V, Bartnikas TB, Pettiglio MA, et al. A competitive enzyme-linked immunosorbent assay specific for murine hepcidin-1: correlation with hepatic mRNA expression in established and novel models of dysregulated iron homeostasis. Haematologica 2015;100:167-177.
26. Torrance JD, Bothwell TH. Tissue iron stores. In: Cook JD, ed. Iron. Methods in Hematology. Vol 1. New York: Churchill Livingstone; 1980: 90-115.
27. Yuan JS, Reed A, Chen F, Stewart CN Jr. Statistical analysis of real-time PCR data. BMC Bioinformatics 2006;7:85.
28. Waheed A, Parkkila S, Zhou XY, Tomatsu S, Tsuchihashi Z, Feder JN, et al. Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc Natl Acad Sci USA 1997;94:12384-12389.
29. Santos M, Schilham MW, Rademakers LH, Marx JJ, de Sousa M, Clevers H. Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man. J Exp Med 1996;184:1975-1985.
30. Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet 2014;46:678-684.
31. Krijt J, Niederkofler V, Salie R, Sefc L, Pelichovska T, Vokurka M, et al. Effect of phlebotomy on hepcidin expression in hemojuvelin-mutant mice. Blood Cells Mol Dis 2007;39:92-95.
32. -/- double knock-out mice. Blood 2004;103:2847-2849.
33. Levy JE, Montross LK, Andrews NC. Genes that modify the hemochromatosis phenotype in mice. J Clin Invest 2000;105:1209-1216.
34. -/- mice: progression with age of iron status and liver pathology. Int J Exp Pathol 2006;87:317-324.
35. Muckenthaler MU, Rodrigues P, Macedo MG, Minana B, Brennan K, Cardoso EM, et al. Molecular analysis of iron overload in beta2-microglobulin-deficient mice. Blood Cells Mol Dis 2004;33:125-131.
36. Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest 2007;117:1933-1939.
37. Wu Q, Sun CC, Lin HY, Babitt JL. Repulsive guidance molecule (RGM) family proteins exhibit differential binding kinetics for bone morphogenetic proteins (BMPs). PLoS One 2012;7:e46307.
38. Kent P, Wilkinson N, Constante M, Fillebeen C, Gkouvatsos K, Wagner J, et al. Hfe and Hjv exhibit overlapping functions for iron signaling to hepcidin. J Mol Med (Berl) 2015;93:489-498.
39. Wu Q, Wang H, An P, Tao Y, Deng J, Zhang Z, et al. HJV and HFE play distinct roles in regulating hepcidin. Antioxid Redox Signal 2015;22:1325-1336.
40. Ramos E, Kautz L, Rodriguez R, Hansen M, Gabayan V, Ginzburg Y, et al. Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice. Hepatology 2011;53:1333-1341.
41. Healey EG, Bishop B, Elegheert J, Bell CH, Padilla-Parra S, Siebold C. Repulsive guidance molecule is a structural bridge between neogenin and bone morphogenetic protein. Nat Struct Mol Biol 2015;22:458-465.
42. Mueller TD. RGM co-receptors add complexity to BMP signaling. Nat Struct Mol Biol 2015;22:439-440.
43. Nohe A, Hassel S, Ehrlich M, Neubauer F, Sebald W, Henis YI, et al. The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. J Biol Chem 2002;277:5330-5338.
44. Rausa M, Pagani A, Nai A, Campanella A, Gilberti ME, Apostoli P, et al. Bmp6 expression in murine liver non parenchymal cells: a mechanism to control their high iron exporter activity and protect hepatocytes from iron overload? PLoS One 2015;10:e0122696.
45. Steinbicker AU, Bartnikas TB, Lohmeyer LK, Leyton P, Mayeur C, Kao SM, et al. Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice. Blood 2011;118:4224-4230.
46. Corradini E, Schmidt PJ, Meynard D, Garuti C, Montosi G, Chen S, et al. BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice. Gastroenterology 2010;139:1721-1729.