The Repulsive Guidance Molecule RGMa Is Involved in the Formation of Afferent Connections in the Dentate Gyrus

Brinks, Henriette; Conrad, Sabine; Vogt, Johannes; Oldekamp, Judit; Sierra, Ana; Deitinghoff, Lutz; Bechmann, Ingo; Álvarez-Bolado, Gonzalo; Heimrich, Bernd; Monnier, Philippe P.; Mueller, Bernhard K.; Skutella, Thomas

doi:10.1523/jneurosci.5296-03.2004

Cited by 84 publications

(71 citation statements)

References 30 publications

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“…Previous reports have shown that RGMa inhibits mammalian CNS neurite outgrowth in vitro (Brinks et al, 2004;Hata et al, 2006;Kubo et al, 2008;Ohshima et al, 2008;Yoshida et al, 2008). To evaluate the involvement of p120GAP in the long-term effects of RGMa, we performed two types of in vitro neurite outgrowth assays.…”

Section: The Involvement Of P120gap In Rgma-induced Neurite Outgrowthmentioning

confidence: 99%

“…It has been demonstrated that RGMa is expressed in the inner molecular layer of the hippocampal dentate gyrus and that it restricts the axonal extension of developmental entorhinal cortical neurons, thereby facilitating appropriate connection with the dentate gyrus (Brinks et al, 2004;Ohshima et al, 2008). Furthermore, a recent study reported that RGMa suppresses neurite outgrowth, branching, and synapse formation in cultured cortical neurons (Yoshida et al, 2008), suggesting that RGMa may contribute to the formation of a precise wiring pattern, such as the entorhino-hippocampal connection, by inhibiting both synapse formation in the inner molecular layer of the dentate gyrus and axonal extension of the entorhinal cortical neurons.…”

Section: Roles Of the Rgma-mediated Ras Inactivation In Neuronal Netwmentioning

confidence: 99%

“…The repulsive guidance molecule (RGM) is a developmental repulsive guidance protein that plays a role in axon pathfinding in chicken temporal retina (Monnier et al, 2002). RGMa, a mammalian homolog of chicken RGM, also shows neurite-repulsive ability, and a previous report has indicated that RGMa restricts the axonal extension of developmental entorhinal cortical neurons, thereby facilitating appropriate connection with the hippocampal dentate gyrus (Brinks et al, 2004;Ohshima et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Inactivation of Ras by p120GAP via Focal Adhesion Kinase Dephosphorylation Mediates RGMa-Induced Growth Cone Collapse

Endo¹,

Yamashita²

2009

J. Neurosci.

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The repulsive guidance molecule RGMa performs several functions in the developing and adult CNSs. RGMa, through its receptor neogenin, induces growth cone collapse and neurite outgrowth inhibition. Here, we demonstrate that RGMa binding to neogenin leads to the inactivation of Ras, which is required for the RGMa-mediated repulsive function in cortical neurons. This signal transduction is mediated by the Ras-specific GTPase-activating protein (GAP) p120GAP. The SH2 domain of p120GAP interacts with focal adhesion kinase (FAK), which is phosphorylated at Tyr-397. When the cells are stimulated with RGMa, FAK undergoes dephosphorylation at Tyr-397 and is dissociated from p120GAP, and this dissociation is followed by an increase in the interaction between p120GAP and GTP-Ras. In addition, the knockdown of p120GAP prevents RGMa-induced growth cone collapse and neurite outgrowth inhibition. Furthermore, RGMa stimulation induces Akt inactivation through p120GAP, and the expression of the constitutively active Akt prevents RGMa-induced growth cone collapse. Thus, RGMa binding to neogenin regulates p120GAP activity through FAK Tyr-397 dephosphorylation, leading to the inactivation of Ras and its downstream effector Akt, and this signal transduction plays a role in the RGMa-mediated repulsive function.

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Section: The Involvement Of P120gap In Rgma-induced Neurite Outgrowthmentioning

confidence: 99%

Section: Roles Of the Rgma-mediated Ras Inactivation In Neuronal Netwmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inactivation of Ras by p120GAP via Focal Adhesion Kinase Dephosphorylation Mediates RGMa-Induced Growth Cone Collapse

Endo¹,

Yamashita²

2009

J. Neurosci.

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“…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).…”

mentioning

confidence: 99%

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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“…Over the past few years, many groups have confirmed the ability of RGMs to induce axon repulsion, neurite growth inhibition, and growth cone collapse using different types of neuron [11,13,29,[43][44][45][46]. The role of RGMs in axon guidance and neurite growth inhibition during development has been shown in frog and chick embryos, while in vivo evidence for the neurite growth inhibitory effects of RGMs in mammals is provided by the ability of RGM blockage to promote central nervous system (CNS) axon regeneration.…”

Section: Ectodomain Shedding Of Neogeninmentioning

confidence: 99%

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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The Repulsive Guidance Molecule RGMa Is Involved in the Formation of Afferent Connections in the Dentate Gyrus

Cited by 84 publications

References 30 publications

Inactivation of Ras by p120GAP via Focal Adhesion Kinase Dephosphorylation Mediates RGMa-Induced Growth Cone Collapse

Inactivation of Ras by p120GAP via Focal Adhesion Kinase Dephosphorylation Mediates RGMa-Induced Growth Cone Collapse

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

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

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