Repulsive Guidance Molecule-a and Central Nervous System Diseases

Abstract

Repulsive guidance molecule-a (RGMa) is a member of glycosylphosphatidylinositol- (GPI-) anchored protein family, which has axon guidance function and is widely involved in the development and pathological processes of the central nervous system (CNS). On the one hand, the binding of RGMa and its receptor Neogenin can regulate axonal guidance, differentiation of neural stem cells into neurons, and the survival of these cells; on the other hand, RGMa can inhibit functional recovery of CNS by inhibiting axonal growth. A number of studies have shown that RGMa may be involved in the pathogenesis of CNS diseases, such as multiple sclerosis, neuromyelitis optica spectrum diseases, cerebral infarction, spinal cord injury, Parkinson's disease, and epilepsy. Targeting RGMa can enhance the functional recovery of CNS, so it may become a promising target for the treatment of CNS diseases. This article will comprehensively review the research progression of RGMa in various CNS diseases up to date.

Figure 1

Mechanisms for RGMa Signal Transduction. (a) The role of N-RGM depends on the release of Neogenin intracellular domain by γ-secretase and LMO4. It has been suggested that Neogenin intracellular domain may enter the nucleus together with LMO4 and regulates gene transcription and growth cone collapse. (b) In general, C-RGM-Neogenin binding can activate RhoA through Unc5 and LARG and inactivate Ras through FAK and p120 RasGAP, thus inducing growth cone collapse and playing the role of axon guidance and regulation of neuronal survival. The binding of C-RGMa with Neogenin inhibits the interaction between Lrig2 and Neogenin. At this time, ADAM17 can cleave Neogenin and cause the extracellular domain of Neogenin to fall off, eventually leading to signal termination. Therefore, LRIG2 and ADAM17 can regulate the sensitivity of neurons to RGMa. (c) In epithelial cells, Neogenin binds to and localizes the wave regulatory complex (WRC), leading to actin nucleation via Arp2/3, which also requires Rac1 to activate the stability of adhesion junctions. (d) RGMa acts as a coreceptor of bone morphogenetic protein (BMP) and has been proposed as a structural bridge between BMP and Neogenin. A recently proposed model suggests that RGMa induces endocytosis of BMP receptor complexes, thereby activating classical Smad signaling. The interaction between RGM and BMP signal transduction has been involved in iron metabolism, bone development, axon regeneration, and so on.