Hepatocyte neogenin is required for hemojuvelin-mediated hepcidin expression and iron homeostasis in mice

Neogenin (NEO1) is a ubiquitously expressed multifunctional transmembrane protein. It interacts with hemojuvelin (HJV), a BMP coreceptor that plays a pivotal role in hepatic hepcidin expression. Earlier studies suggest that the function of HJV relies on its interaction with NEO1. However, the role of NEO1 in iron homeostasis remains controversial because of the lack of an appropriate animal model. Here, we generated a hepatocyte-specific Neo1 knockout (Neo1(fl/fl);Alb-Cre(+)) mouse model that circumvented the developmental and lethality issues of the global Neo1 mutant. Results show that ablation of hepatocyte Neo1 decreased hepcidin expression and caused iron overload. This iron overload did not result from altered iron utilization by erythropoiesis. Replacement studies revealed that expression of the Neo1(L1046E) mutant that does not interact with Hjv, was unable to correct the decreased hepcidin expression and high serumiron in Neo1(fl/fl);Alb-Cre(+) mice. In Hjv(-/-) mice, expression of Hjv(A183R) mutant that has reduced interaction with Neo1, also displayed a blunted induction of hepcidin expression. These observations indicate that Neo1-Hjv interaction is essential for hepcidin expression. Further analyses suggest that the Hjv binding triggered the cleavage of the Neo1 cytoplasmic domain by a protease, which resulted in accumulation of truncated Neo1 on the plasmamembrane. Additional studies did not support that Neo1 functions by inhibitingHjv shedding as previously proposed. Together, our data favor a model in which Neo1 interaction with Hjv leads to accumulation of cleaved Neo1 on the plasma membrane, where Neo1 acts as a scaffold to induce the Bmp signaling and hepcidin expression.

Automated summary

Neogenin (NEO1) is an important protein that interacts with hemojuvelin (HJV) to regulate hepcidin expression and iron homeostasis. Knocking out hepatocyte-specific Neo1 leads to decreased hepcidin expression and iron overload, highlighting the essential role of Neo1-Hjv interaction in hepcidin regulation.