Mouse RGMs : a three protein family with diverse function and localization

Abstract

Identification and Functional Characterization of the Mouse RGM Family In the developing chick visual system, axons project from the retina to the optic tectum in a stereotypical manner to produce a topographic map. This topography conserves spatial information registered by the retina by preserving nearest neighbour relationships among the termination zones of projecting retinal ganglion cells (RGCs). Thus, two RGCs which lie next to each other in the retina will have axonal projections terminating very near each other within the optic tectum, while RGCs which are at opposite sides of the retina will have diametrically opposed termination zones. The establishment of the retinotectal topographic map relies on tight spatial and temporal control of molecules which control axon guidance, branching and termination. One such molecule, proposed to inhibit axonal growth into the tectum, Repulsive Guidance Molecule (RGM), has been implicated in control of RGC axon termination along the anterior-posterior axis of the chick optic tectum. We discovered three mouse genes homologous to chick RGM, the protein products of which share similarities in structure, proteolytic cleavage and putative GPI-anchoring, but which differ in spatio-temporal expression, cell surface targeting and most importantly function. Two members of this gene family (mRGMa and mRGMb) are expressed in the nervous system. In the visual system, mRGMa is prominently expressed in the superior colliculus, the mouse equivalent of the chick optic tectum, and mRGMb in the retinal ganglion cell layer at the time of anterior-posterior targeting of RGC axons. The third member of the family, mRGMc (independently identified as hemojuvelin (hjv)), is expressed most strongly in skeletal muscles, but also in liver and heart. Surprisingly, neither mRGMa nor mRGMb are expressed in a gradient in the superior colliculus. Moreover, disruption of either mRGMa or mRGMb does not affect the anterior-posterior targeting of the topographic map. Instead, half of mRGMa mutant mice show a severe defect in cephalic neural tube closure, known as exencephaly, while the remaining animals appear phenotypically normal. All mRGMb mutant mice die at approximately three weeks of age for unknown reasons, indicating an essential requirement for RGMb, however its specific function remains a mystery. Mice deficient in mRGMc suffer from severe iron overload. This condition is similar to juvenile hemochromatosis, a human disease resulting from mutations in the gene HFE2, the human homologue of mRGMc. At a molecular level, the severity of the disease state in Hjv mutant mice can be explained by dramatic decrease in hepcidin, a negative regulator of iron absorption produced by the liver in response to ingested iron. Interestingly, these mice retain the ability to produce hepcidin in response to inflammatory stimuli. Furthermore, induction of inflammatory response causes a rapid downregulation of Hjv in wildtype mice. Our findings define a key role for Hjv in dietary iron-sensing and reveal how Hjv acts a switch during inflammation, to prevent conflict between the pathway controlling dietary iron homeostasis and that controlling inflammatory iron sequestration as a defense mechanism against infection.