Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver.
Although hepcidin expression was shown to be induced by the BMP/Smad signaling pathway, it is not yet known how iron regulates this pathway and what its exact molecular targets are. We therefore assessed genome-wide liver transcription profiles of mice of 2 genetic backgrounds fed iron-deficient, -balanced, or -enriched diets. Among 1419 transcripts significantly modulated by the dietary iron content, 4 were regulated similarly to the hepcidin genes Hamp1 and Hamp2. They are coding for Bmp6, Smad7, Id1, and Atoh8 all related to the Bmp/Smad pathway. As shown by Western blot analysis, variations in Bmp6 expression induced by the diet iron content have for functional consequence similar changes in Smad1/5/8 phosphorylation that leads to formation of heteromeric complexes with Smad4 and their translocation to the nucleus. Gene expression variations induced by secondary iron deficiency or iron overload were compared with those consecutive to Smad4 and Hamp1 deficiency. Iron overload developed by Smad4- and Hamp1-deficient mice also increased Bmp6 transcription. However, as shown by analysis of mice with liver-specific disruption of Smad4, activation of Smad7, Id1, and Atoh8 transcription by iron requires Smad4. This study points out molecules that appear to play a critical role in the control of systemic iron balance.
Institut National de la Santé et de la Recherche Médicale, U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
Léon
L
Kautz
Delphine
D
Meynard
Annabelle
A
Monnier
Valérie
V
Darnaud
Régis
R
Bouvet
Rui-Hong
RH
Wang
Chiuxia
C
Deng
Sophie
S
Vaulont
Jean
J
Mosser
Hélène
H
Coppin
Marie-Paule
MP
Roth
D021581:Active Transport, Cell Nucleus; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D004032:Diet; D020869:Gene Expression Profiling; D007501:Iron / Q000502:physiology*; D019190:Iron Overload / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics* / Q000378:metabolism; D051898:Smad1 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000172:deficiency / Q000502:physiology; D051902:Smad5 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics; D051904:Smad8 Protein / Q000378:metabolism; D014158:Transcription, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D007501:Iron; D051785:Smad Proteins; D051898:Smad1 Protein; D051901:Smad4 Protein; D051902:Smad5 Protein; D051906:Smad7 Protein; D051904:Smad8 Protein; C449163:Atoh8 protein, mouse; C525817:Bmp6 protein, mouse; C497401:Smad1 protein, mouse; C490810:Smad4 protein, mouse; C497798:Smad5 protein, mouse; C497807:Smad7 protein, mouse