D F Wallace1, L Summerville, P E Lusby, V N Subramaniam. 1. The Membrane Transport Laboratory, Cancer and Cell Biology Division, The Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
Abstract
BACKGROUND: Transferrin receptor 2 (TfR2) is a key molecule involved in the regulation of iron homeostasis. Mutations in humans cause type 3 haemochromatosis and a targeted mutation in mice leads to iron overload with a similar phenotype. We have previously described the generation of a complete TfR2-knockout (KO) mouse. AIMS: The aims of this study were to determine the phenotype and analyse expression of iron related molecules in the liver, duodenum, and spleen of homozygous TfR2-KO, heterozygous, and wild-type mice. METHODS: Serum and tissue iron levels were determined in 10 week old male mice. Expression of iron related mRNA transcripts were analysed in the liver, duodenum, and spleen using real time polymerase chain reaction. Expression of iron related proteins in the liver were analysed by immunoblotting and immunohistochemistry. RESULTS: Homozygous TfR2-KO mice had no TfR2 protein expression and developed significant iron overload typical of TfR2 associated haemochromatosis. In the liver of TfR2-KO mice there was no upregulation of hepcidin mRNA or prohepcidin protein in response to iron loading. CONCLUSIONS: Our results suggest that TfR2 is required for iron regulated expression of hepcidin and is involved in a pathway related to Hfe and hemojuvelin.
BACKGROUND:Transferrin receptor 2 (TfR2) is a key molecule involved in the regulation of iron homeostasis. Mutations in humans cause type 3 haemochromatosis and a targeted mutation in mice leads to iron overload with a similar phenotype. We have previously described the generation of a complete TfR2-knockout (KO) mouse. AIMS: The aims of this study were to determine the phenotype and analyse expression of iron related molecules in the liver, duodenum, and spleen of homozygous TfR2-KO, heterozygous, and wild-type mice. METHODS: Serum and tissue iron levels were determined in 10 week old male mice. Expression of iron related mRNA transcripts were analysed in the liver, duodenum, and spleen using real time polymerase chain reaction. Expression of iron related proteins in the liver were analysed by immunoblotting and immunohistochemistry. RESULTS: Homozygous TfR2-KO mice had no TfR2 protein expression and developed significant iron overload typical of TfR2 associated haemochromatosis. In the liver of TfR2-KO mice there was no upregulation of hepcidin mRNA or prohepcidin protein in response to iron loading. CONCLUSIONS: Our results suggest that TfR2 is required for iron regulated expression of hepcidin and is involved in a pathway related to Hfe and hemojuvelin.
Authors: G Nicolas; M Bennoun; I Devaux; C Beaumont; B Grandchamp; A Kahn; S Vaulont Journal: Proc Natl Acad Sci U S A Date: 2001-07-10 Impact factor: 11.205
Authors: R E Fleming; M C Migas; C C Holden; A Waheed; R S Britton; S Tomatsu; B R Bacon; W S Sly Journal: Proc Natl Acad Sci U S A Date: 2000-02-29 Impact factor: 11.205
Authors: Robert E Fleming; John R Ahmann; Mary C Migas; Abdul Waheed; H Phillip Koeffler; Hiroshi Kawabata; Robert S Britton; Bruce R Bacon; William S Sly Journal: Proc Natl Acad Sci U S A Date: 2002-07-19 Impact factor: 11.205
Authors: Irene Pichler; Cosetta Minelli; Serena Sanna; Toshiko Tanaka; Christine Schwienbacher; Silvia Naitza; Eleonora Porcu; Cristian Pattaro; Fabio Busonero; Alessandra Zanon; Andrea Maschio; Scott A Melville; Maria Grazia Piras; Dan L Longo; Jack Guralnik; Dena Hernandez; Stefania Bandinelli; Elmar Aigner; Anthony T Murphy; Victor Wroblewski; Fabio Marroni; Igor Theurl; Carsten Gnewuch; Eric Schadt; Manfred Mitterer; David Schlessinger; Luigi Ferrucci; Derrick R Witcher; Andrew A Hicks; Günter Weiss; Manuela Uda; Peter P Pramstaller Journal: Hum Mol Genet Date: 2010-12-28 Impact factor: 6.150
Authors: Junwei Gao; Juxing Chen; Ivana De Domenico; David M Koeller; Cary O Harding; Robert E Fleming; Dwight D Koeberl; Caroline A Enns Journal: Blood Date: 2010-02-22 Impact factor: 22.113
Authors: Cameron J McDonald; Malcolm K Jones; Daniel F Wallace; Lesa Summerville; Sujeevi Nawaratna; V Nathan Subramaniam Journal: PLoS One Date: 2010-03-09 Impact factor: 3.240