Repulsive guidance molecule-A (RGM-A) inhibits leukocyte migration and mitigates inflammation

Mirakaj, Valbona; Brown, S. Lori; Laucher, Stefanie; Steinl, Carolin; Klein, Gerd; Köhler, David; Skutella, Thomas; Meisel, Christian; Brommer, Benedikt; Rosenberger, Peter; Schwab, Jan M.

doi:10.1073/pnas.1015605108

Cited by 55 publications

(58 citation statements)

References 33 publications

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“…Instead, as RGMa-neogenin cell spreading was enhanced by Noggin treatment, we report an unexpected deregulating activity of BMP. Our results are consistent with a model whereby BMP activity is not necessary for RGManeogenin function, as reported recently in the immune system (34). It remains to be determined whether RGMa interacts with neogenin in cis or in trans to mediate cell adhesion.…”

Section: Discussionsupporting

confidence: 81%

Novel Roles of the Chemorepellent Axon Guidance Molecule RGMa in Cell Migration and Adhesion

Lah

Key

2012

Molecular and Cellular Biology

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The repulsive guidance molecule A (RGMa) is a contact-mediated axon guidance molecule that has significant roles in central nervous system (CNS) development. Here we have examined whether RGMa has novel roles in cell migration and cell adhesion outside the nervous system. RGMa was found to stimulate cell migration from Xenopus animal cap explants in a neogenindependent and BMP-independent manner. RGMa also stimulated the adhesion of Xenopus animal cap cells, and this adhesion was dependent on neogenin and independent of calcium. To begin to functionally characterize the role of specific domains in RGMa, we assessed the migratory and adhesive activities of deletion mutants. RGMa lacking the partial von Willebrand factor type D (vWF) domain preferentially perturbed cell adhesion, while mutants lacking the RGD motif affected cell migration. We also revealed that manipulating the levels of RGMa in vivo caused major migration defects during Xenopus gastrulation. We have revealed here novel roles of RGMa in cell migration and adhesion and demonstrated that perturbations to the homeostasis of RGMa expression can severely disrupt major morphogenetic events. These results have implications for understanding the role of RGMa in both health and disease. Repulsive guidance molecule (RGM) was first identified in the embryonic chick retinotectal system as a chemorepulsive molecule for retinal axons (35). Subsequently, three different RGMs (RGMa, RGMb, and RGMc) were identified in mouse, and each was found to have a unique spatiotemporal expression pattern (41,48). RGMa is a membrane-bound protein with ϳ430 amino acid (aa) residues that has a glycosylphosphatidylinositol (GPI)-anchored C-terminal domain and a conventional N-terminal signal peptide (35,48). It is cysteine rich and contains a putative autoproteolytic cleavage site, a single tri-amino acid motif, ArgGly-Asp (RGD), a partial von Willebrand factor type D (vWF) domain, and two hydrophobic domains at the N and C termini. These key molecular structures, except for the RGD domain (which is absent in RGMb in most animal models), are shared by all members of the RGM family (5, 35). A conserved RSDSPEI sequence, 5= to the partial von Willebrand type D domain, is present within RGMa from mammals, frogs, and birds. To date, the roles of these different RGM domains remain unknown.The first RGM receptor was identified by cell surface binding of chick RGM to cells expressing neogenin, a member of the immunoglobulin superfamily of transmembrane receptors (31,35,43,(54)(55)(56)(57). RGMa-neogenin interactions are involved in axon guidance in the developing visual system and in axon tract formation in the embryonic brain in vivo (31,35,54,55,57,58). RGMa also has chemorepulsive activity during laminar patterning of the developing mouse dentate gyrus in vitro (4). Interestingly, RGMa knockout mice did not show an abnormality in retinal topography but displayed an exencephalic phenotype in ϳ50% of embryos, suggesting that RGMa plays a role in neural tube closure (37). We and others...

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Section: Discussionsupporting

confidence: 81%

Novel Roles of the Chemorepellent Axon Guidance Molecule RGMa in Cell Migration and Adhesion

Lah

Key

2012

Molecular and Cellular Biology

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“…These experiments suggest that blocking RGMa may reduce inflammatory disease. However, another study reported that RGMa inhibits migration of RGMa-expressing leukocytes (T and B lymphocytes, monocytes, and granulocytes) via chemo-and contact repulsion and RGMa suppressed inflammation in a zymosan-induced peritonitis model [33]. These seemingly contrasting results might be explained by the different types of models used and by differences in underlying signaling complexes.…”

Section: Immune Cell Signaling and Multiple Sclerosismentioning

confidence: 99%

“…These data show that RGMs are a structural bridge between Neogenin and BMP signaling, and inform that a clustering mechanism may be important in the activation of these signaling pathways. [29,30], early stages of neurulation [31], CD4+ T cell adhesion and activation [32], and leukocyte migration [33]. This can be either contact dependent (adhesive) or mediated by gradients established by cleaved extracellular RGM isoforms.…”

Section: Structural Insight Into Ligand-receptor Interactionsmentioning

confidence: 99%

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RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

Siebold

Yamashita

Monnier

et al. 2017

Trends in Cell Biology

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Although originally discovered as neuronal growth cone-collapsing factors, repulsive guidance molecules (RGMs) are now known as key players in many fundamental processes, such as cell migration, differentiation, iron homeostasis, and apoptosis, during the development and homeostasis of many tissues and organs, including the nervous, skeletal, and immune systems. Furthermore, three RGMs (RGMa, RGMb/DRAGON, and RGMc/hemojuvelin) have been linked to the pathogenesis of various disorders ranging from multiple sclerosis (MS) to cancer and juvenile hemochromatosis (JHH). While the molecular details of these (patho) biological effects and signaling modes have long remained unknown, recent studies unveil several exciting and novel aspects of RGM processing, ligand-receptor interactions, and downstream signaling. In this review, we highlight recent advances in the mechanisms-of-action and function of RGM proteins. RGMs: A Small Gene Family with Widespread EffectsGuidance molecules, initially observed to direct growing axons during embryogenesis [1], also have crucial roles in the morphogenesis and homeostasis of non-neuronal tissues by controlling a plethora of cellular processes, ranging from cell division and migration to differentiation and death. Figure 1A). Each RGM displays tissuespecific expression, is subjected to distinct biosynthetic and processing steps, and has not only unique, but also shared biological functions [2]. RGMs bind the type 1 transmembrane protein Neogenin ( Figure 1A) and many of the reported biological effects of RGMs rely on Neogenin receptor functions, such as axon guidance or neuronal survival [3,4]. RGMs also serve as co-receptors for bone morphogenetic proteins (BMPs) ( Figure 1A) to regulate iron metabolism, skeletal development [5-10] and axon regeneration [11]. In addition to these physiological roles, and as discussed below, RGMs have been implicated in various diseases and are considered to be promising targets in the treatment of MS, spinal cord injury, stroke, anemia, and inflammation [5,[11][12][13][14][15].Although the molecular mechanisms underlying the biological effects and signaling modes of RGMs have long remained unknown, recent work has unveiled several exciting and novel aspects of RGM processing, ligand-receptor interactions, and downstream signaling. These insights include high-resolution structural data of binary or tertiary protein complexes, the unique processing of RGMs into protein fragments with distinct functions, and the identification of a novel molecular mechanism to control ligand-induced ectodomain shedding of Neogenin. In this review, we discuss recent highlights in RGM research, from novel structural data to previously unexplored signaling mechanisms and cellular functions. Structural Insight into Ligand-Receptor InteractionsFor many years, RGMs posed a molecular puzzle because of a general lack of structural homologies to any known protein fold. Recent studies have shed light on their 3D structure and identified two ordered and disulfide-stabiliz...

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“…[1][2][3] Thought to be exclusively expressed in the central nervous system (CNS), RGMa has been recently found to be expressed in spleen, monocytes, and lymphocytes, which suggests a role within the immune system. 4 Futhermore, a study on multiple sclerosis (MS) and a mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), in which dendritic cells (DCs) play an irreplaceable role, demonstrates that application of a RGMa-neutralizing antibody can reduce the clinical signs and immune responses of EAE by DCs. 5 Consistent with the study, we found that the expression of RGMa was induced in mature DCs.…”

Section: Introductionmentioning

confidence: 99%

Repulsive guidance molecule a blockade exerts the immunoregulatory function in DCs stimulated with ABP and LPS

Gao

Zhai

et al. 2016

Human Vaccines & Immunotherapeutics

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Repulsive guidance molecule a (RGMa) is an axonal guidance molecule that has recently found to exert function in immune system. This study evaluated the function of RGMa in modulation of dendritic cells (DCs) function stimulated with Achyranthes bidentata polysaccharide (ABP) and lipopolysaccharide (LPS) using a RGMa-neutralizing antibody. Compared with the Control-IgG/ABP and Control-IgG/LPS groups, DCs in the Anti-RGMa/ABP and Anti-RGMa/LPS groups 1) showed small, round cells with a few cell processes and organelles, and many pinocytotic vesicles; 2) had decreased MHC II, CD86, CD80, and CD40 expression; 3) displayed the decreased IL-12p70, IL-1b and TNF-a levels and increased IL-10 secretion; 4) had a high percentage of FITC-dextran uptake; and 5) displayed a reduced ability to drive T cell proliferation and reinforced T cell polarization toward a Th2 cytokine pattern. We conclude that DCs treated with RGMa-neutralizing antibodies present with tolerogenic and immunoregulatory characteristics, which provides new insights into further understanding of the function of RGMa.

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Repulsive guidance molecule-A (RGM-A) inhibits leukocyte migration and mitigates inflammation

Cited by 55 publications

References 33 publications

Novel Roles of the Chemorepellent Axon Guidance Molecule RGMa in Cell Migration and Adhesion

Novel Roles of the Chemorepellent Axon Guidance Molecule RGMa in Cell Migration and Adhesion

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

Repulsive guidance molecule a blockade exerts the immunoregulatory function in DCs stimulated with ABP and LPS

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