Homozygous loss of Tmprss6 up-regulates hepatic Bmp/Smad signaling in Hfe^−/− mice. (A-F) Analysis of mRNA expression of genes involved in hepatic Bmp/Smad signaling in 8-week-old female mice of selected Hfe-Tmprss6 genotype combinations. Graphed is the mean mRNA expression of hepcidin (Hamp; A), Smad7 (B), Id1 (C), Bmp6 (D), Tmprss6 (E), and Hfe (F), relative to β-actin (Actb). mRNA expression ratios are normalized to an Hfe^+/+Tmprss6^+/+ mean value of 1. For each parameter shown, the number of mice per genotype analyzed was 7 Hfe^+/+Tmprss6^+/+, 5 Hfe^+/+Tmprss6^−/−, 8 Hfe^−/−Tmprss6^+/+, 8 Hfe^−/−Tmprss6^+/−, and 6 Hfe^−/−Tmprss6^−/− mice. Error bars represent SD. NS indicates not significant. In panel E, the low level of Tmprss6 mRNA detected in mice with homozygous loss of Tmprss6 reflects the known, low-level expression of a partial transcript from the targeted Tmprss6 locus.²⁶