A working model for hepcidin regulation by iron in the mouse. (A) Bmp6, whose expression is induced by iron, binds to type I and II receptors and to the coreceptor, hemojuvelin (Hjv). The constitutively active kinase domains of type II receptors phosphorylate type I receptors, and this in turn activates the Smad signaling pathway through phosphorylation of receptor Smads (Smad1, Smad5, and Smad8). These associate with co-Smads (Smad4) to form a heteromeric complex that translocates to the nucleus and stimulates the expression of a wide range of target genes, including the genes coding for Id1, Smad7, and possibly also Atoh8. Hypothetical roles for Id1, Smad7, and Atoh8 are presented on panels B through E. (B) When dietary iron availability is low, hepcidin transcription is repressed by specific basic-loop-helix (bHLH) repressors. (C) When the diet iron content increases, inhibitor of differentiation proteins Id1 are synthesized. These are known to associate with bHLH proteins and prevent them from binding DNA. By sequestering the bHLH repressors, Id1 proteins may stop them from achieving their inhibiting functions on the hepcidin promoter. (D) Iron overload also increases Smad 7, which could enhance Atoh8 activity as it does for another bHLH transcription activator, MyoD. (E) The hepcidin promoter contains several E-boxes known to interact with bHLH transcription factors and further investigation will determine whether Atoh8 binds to and activates the hepcidin promoter.