Repulsive Guidance Molecules and Receptors

In mammals, the Repulsive Guidance Molecule (RGM) family consists of three glycoproteins which have discrete expression patterns and functions (RGM-A, RGM-B, and RGM-C). RGMs are known to function through Neogenin, a homologue of the Netrin receptor deleted in colon cancer (DCC). Neogenin is a multifunctional receptor that can mediate Netrin-induced attraction and RGM-induced repulsion. In addition to Neogenin, recent studies suggest that RGM-A induced growth cone collapse requires co-receptor UNC5, and that signal transduction involves the Leukemia-associated RhoGEF (LARG).

RGM-A was discovered in 2002, as a chemorepulsive signal for temporal retinal axons in chick anterior tectum. Additional studies have shown that RGM-A expression inhibits axon regeneration following injury, an effect that can be neutralized by RGM-A antibody administration. RGM-A is also known to affect neural tube closure, with loss of function mice exhibiting exencephaly, a severe developmental defect. Other studies suggested that Neogenin is a dependence receptor and that RGM-A promotes cell survival by inhibiting Neogenin-induced apoptotic cell death. Because RGM-A and Neogenin are expressed in neurogenic areas of mouse and human adult forebrain, RGM-A signaling has also been implicated in neurogenesis.

RGM-B, also know as DRAGON (turned ON in DRG), is expressed throughout the CNS in an almost non-overlapping distribution to RGM-A but does not exert a repulsive guidance effect. RGM-C/Hemojuvelin is not expressed in the CNS. Mutations in the gene that encode RGM-C result in juvenile hemochromatosis, an autosomal-recessive disease characterized by early onset systemic iron overload.