Spinal cord injury‐induced lesional expression of the repulsive guidance molecule (RGM)

Schwab, Jan M.; Conrad, Sabine; Monnier, Philippe P.; Julien, Sylvie; Mueller, Bernhard K.; Schluesener, Hermann J.

doi:10.1111/j.1460-9568.2005.03962.x

Cited by 105 publications

(74 citation statements)

References 34 publications

(57 reference statements)

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“…This is certainly not the case with PC12 cells, which express neogenin but not RGMs and do not die under these conditions. Schwab et al (38,39) observed spinal cord injury-induced lesional expression of the RGM. Lesional RGM expression was frequently confined to hypertrophic ␤-APP ϩ and RhoA ϩ neurites/retraction bulbs.…”

Section: Discussionmentioning

confidence: 99%

Neogenin-RGMa Signaling at the Growth Cone Is Bone Morphogenetic Protein-independent and Involves RhoA, ROCK, and PKC

Conrad¹,

Genth

Hofmann

et al. 2007

Journal of Biological Chemistry

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The repulsive guidance molecule RGMa has been shown to induce outgrowth inhibition of neurites by interacting with the transmembrane receptor neogenin. Here we show that RGMainduced growth cone collapse is mediated by activation of the small GTPase RhoA, its downstream effector Rho kinase and PKC. In contrast to DRG cultures from neogenin ؊/؊ mice, in which no RGMa-mediated growth cone collapse and activation of RhoA occurred, treatment of wild type DRG neurites with soluble RGMa led to a marked activation of RhoA within 3 min followed by collapse, but left Rac1 and Cdc42 unaffected. Furthermore, preincubation of DRG axons with the bone morphogenetic protein (BMP) antagonist noggin had no effect on RGMa-mediated growth cone collapse, implying that the role of RGM in axonal guidance is neogenin-and not BMP receptordependent. Pretreatment with 1) C3-transferase, a specific inhibitor of the Rho GTPase; 2) Y-27632, a specific inhibitor of Rho kinase; and 3) Gö6976, the general PKC inhibitor, strongly inhibited the collapse rate of PC12 neurites. Growth cone collapse induced by RGMa was abolished by the expression of dominant negative RhoA, but not by dominant negative Rac1. In contrast to RGMa, netrin-1 induced no growth cone retraction but instead reduced RGMa-mediated growth cone collapse. These results suggest that activation of RhoA, Rho kinase, and PKC are physiologically relevant and important elements of the RGMa-mediated neogenin signal transduction pathway involved in axonal guidance.During the development of the central and peripheral nervous system, target-derived axon extension is guided by attractive and repulsive diffusible or membrane-bound factors acting over short and long distances (1). During axonal chemorepulsion, repulsive guidance cues hinder neurite outgrowth, turn growth cones away from a guidance cue, and in the case of growth cone collapse induce a dramatic retraction of the growth cone. Although the repulsive guidance molecules (RGM) 2 and their receptor neogenin have been identified as guidance factors (2-6), the cytoplasmic signaling mechanisms responsible for triggering neogenin-mediated and -directed growth cone collapse remain to be clarified. Recently Hata et al.(7) demonstrated that neurite extension of cerebellar granule neurons was inhibited when these cells were plated on a monolayer of RGMa overexpressing cells and that this effect can be blocked with RhoA and Rho kinase inhibitors. Furthermore, increased amounts of GTP-RhoA were observed in these primary neurons after the addition of soluble RGMa.Neogenin, which is expressed by growing nerve cells in the developing vertebrate brain, consists of four immunoglobulinlike domains followed by six fibronectin type III domains, a transmembrane domain, and an intracellular domain (4, 8 -10). Neogenin is closely related to the netrin-1 receptor deleted in colorectal carcinoma (DCC); it binds RGMa and, to a lesser extent, netrin-1 directly (4, 11). Although its functional role in neuronal development has not been elucidated in detail, hi...

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Section: Discussionmentioning

confidence: 99%

Neogenin-RGMa Signaling at the Growth Cone Is Bone Morphogenetic Protein-independent and Involves RhoA, ROCK, and PKC

Conrad¹,

Genth

Hofmann

et al. 2007

Journal of Biological Chemistry

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“…Several studies have been performed to clarify the role of RGMA in the degenerating/non-regenerating processes of CNS injuries: Schwab et al showed that RGM+ cells accumulated in lesioned and peri-lesional areas after spinal cord injury (SCI), and several glial and non-glial cells and tissues (including the mature and maturing scar) showed RGM immunoreactivity [21]. It was also shown in rats after SCI that inhibition of RGM enhanced growth of injured axons, promoted functional recovery [22], and induced synaptic rearrangements of spared axonal projections [23].…”

Section: Introductionmentioning

confidence: 99%

RGMA and neogenin protein expression are influenced by lens injury following optic nerve crush in the rat retina

Schnichels

Heiduschka

Julien

2011

Graefes Arch Clin Exp Ophthalmol

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Although a difference in the localization of RGMA is not obvious, the difference in the amount of RGMA is striking, the higher amount of RGMA in the retinae of ONC + LI rats compared to ONC rats indicates a role for RGMA during degeneration/regeneration processes. Our results are consistent with several reported neuroprotective effects of RGMA. Our new data showing the upregulation of RGMA after ONC in our regenerating model (plus LI) confirm these findings conducted in different settings.

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“…In the healthy adult human brain, immunohistochemistry with a pan-RGM antibody revealed that RGM proteins are located on perikarya of some neurons, chorioid plexus, smooth muscle of the vasculature, endothelial cells and on oligodendrocytes and white matter fibre tracts (Schwab et al 2005a). A similar staining pattern was also observed in the rat brain, suggesting that RGM proteins could act in concert with myelin-associated inhibitors Nogo-A, MAG and OMGp to restrict or prevent plasticity of neurites in the adult mammalian CNS (Schwab et al 2005b). This evolutionary conserved expression pattern of RGM proteins provides evidence that RGM proteins are potential inhibitors of neuroregeneration and it was therefore important to analyse their expression in the injured or stroke-damaged human brain.…”

Section: Role Of Repulsive Guidance Molecules In Adult Vertebrate Cnsmentioning

confidence: 64%

The role of repulsive guidance molecules in the embryonic and adult vertebrate central nervous system

Mueller¹,

Yamashita

Schaffar³

et al. 2006

Phil. Trans. R. Soc. B

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During the development of the nervous system, outgrowing axons often have to travel long distances to reach their target neurons. In this process, outgrowing neurites tipped with motile growth cones rely on guidance cues present in their local environment. These cues are detected by specific receptors expressed on growth cones and neurites and influence the trajectory of the growing fibres. Neurite growth, guidance, target innervation and synapse formation and maturation are the processes that occur predominantly but not exclusively during embryonic or early post-natal development in vertebrates. As a result, a functional neural network is established, which is usually remarkably stable. However, the stability of the neural network in higher vertebrates comes at an expensive price, i.e. the loss of any significant ability to regenerate injured or damaged neuronal connections in their central nervous system (CNS). Most importantly, neurite growth inhibitors prevent any regenerative growth of injured nerve fibres. Some of these inhibitors are associated with CNS myelin, others are found at the lesion site and in the scar tissue. Traumatic injuries in brain and spinal cord of mammals induce upregulation of embryonic inhibitory or repulsive guidance cues and their receptors on the neurites. An example for embryonic repulsive directional cues re-expressed at lesion sites in both the rat and human CNS is provided with repulsive guidance molecules, a new family of directional guidance cues.

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Spinal cord injury‐induced lesional expression of the repulsive guidance molecule (RGM)

Cited by 105 publications

References 34 publications

Neogenin-RGMa Signaling at the Growth Cone Is Bone Morphogenetic Protein-independent and Involves RhoA, ROCK, and PKC

Neogenin-RGMa Signaling at the Growth Cone Is Bone Morphogenetic Protein-independent and Involves RhoA, ROCK, and PKC

RGMA and neogenin protein expression are influenced by lens injury following optic nerve crush in the rat retina

The role of repulsive guidance molecules in the embryonic and adult vertebrate central nervous system

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