Smad7, Id1, and Atoh8 in the mouse liver Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6,

Abstract 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 two genetic backgrounds fed iron-deficient, -balanced, or -enriched diets. Among 1419 transcripts significantly modulated by the dietary iron content, four were regulated similarly to the hepcidin genes Hamp1 and Hamp2 . They are coding for Bmp6, Smad7, Id1, and Atoh8 that are 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