CRMP-2 Is Involved in Axon Growth Inhibition Induced by RGMa In Vitro and In Vivo

Wang, Tianzhu; Wu, Xiaohui; Chen, Yin; Klebe, Damon; Zhang, Junyi; Qin, Xinyue

doi:10.1007/s12035-012-8385-3

Cited by 28 publications

(29 citation statements)

References 32 publications

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“…As a result, neurological degeneration was blocked, thereby suggesting that RGMa participated in axonal growth inhibition after central nervous system injury. Recent in vitro functional studies using loss of function models have evidenced the direct involvement of specific guidance molecules in determining the growth and targeting of axonal fibers (15,43). Thus, in the absence of these guidance molecules, the growing axons lose their directional sense and result in disturbances in the well-defined anatomical construction of axonal networks in the hippocampus (44).…”

Section: Discussionmentioning

confidence: 99%

Changes of fractional anisotropy and RGMa in crossed cerebellar diaschisis induced by middle cerebral artery occlusion

et al. 2019

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Crossed cerebellar diaschisis (CCD) is the phenomenon of hypoperfusion and hypometabolism of the contralateral cerebellar hemisphere caused by dysfunction of the associated supratentorial region. The aim of the present study was to analyze the changes in fractional anisotropy (FA) in CCD induced by middle cerebral artery occlusion (MCAO) using magnetic resonance-diffusion tensor imaging (MR-DTI). Furthermore, the role of repulsive guidance molecule a (RGMa) in CCD was assessed by measuring RGMa expression using histochemical analysis. In the present study, the cerebellar hemisphere was serially scanned with T2-weighted, serial diffusion-weighted and diffusion tensor (DT) imaging using a 3.0T GE Signa HDxt Scanner to analyze the changes in FA over 72 h. Subsequently, immunohistochemistry analyses of the corresponding cerebellar hemisphere sections were performed to assess the expression of RGMa. Results indicated that FA of both sides of the cerebellar hemisphere, particularly that of the contralateral cerebellar hemisphere (right side) derived from DTI, was reduced during the 72-h time period following MCAO, and the decrease was maximal and statistically significant at 12 h (P<0.05). Immunohistochemistry analysis revealed a significant increase in the expression of RGMa protein in the affected region of the contralateral cerebellar hemisphere (right side) at 24 h following MCAO injury (P<0.05). Furthermore, the expression of RGMa and FA was negatively correlated in MCAO (P<0.05). The results suggest that MR-DTI is an important assessment to evaluate changes of FA in CCD induced by MCAO. Furthermore, the present results suggest that RGMa, which was negatively correlated with FA in MCAO rats, may serve an important role in CCD.

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Section: Discussionmentioning

confidence: 99%

Changes of fractional anisotropy and RGMa in crossed cerebellar diaschisis induced by middle cerebral artery occlusion

et al. 2019

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“…Some in vitro studies suggested that reduced GSK3β activity is required for axon formation, elongation or decreased retraction [28,32-36], in a CRMP-2-dependent mechanism [28,36]. Accordingly, in vivo studies using GSK3β inhibitors showed increased axon regeneration following spinal cord injury [14].…”

Section: Discussionmentioning

confidence: 99%

“…Besides being phosphorylated by GSK3β at Thr514 [39], CRMP-2 is also phosphorylated by Rho-associated protein kinase (ROCK) but at an alternative residue, Thr555 [48], downstream of both Myelin-associated glycoprotein (MAG) and Nogo-66 [49]. Interestingly, repulsive guidance molecule A (RGMa) inhibits axon growth by inducing CRMP-2 phosphorylation via both ROCK and GSK3β signaling [36]. However, in that study, details on which CRMP-2 phosphorylation (Thr514 or Thr555) was assessed are lacking, and GSK3β inhibition was performed in cultured neurons using a GSK3β antibody in the media and not a specific cell-permeable GSK3β inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Neuronal deletion of GSK3β increases microtubule speed in the growth cone and enhances axon regeneration via CRMP-2 and independently of MAP1B and CLASP2

Liz¹,

Mar

Santos³

et al. 2014

BMC Biol

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BackgroundIn the adult central nervous system, axonal regeneration is abortive. Regulators of microtubule dynamics have emerged as attractive targets to promote axonal growth following injury as microtubule organization is pivotal for growth cone formation. In this study, we used conditioned neurons with high regenerative capacity to further dissect cytoskeletal mechanisms that might be involved in the gain of intrinsic axon growth capacity.ResultsFollowing a phospho-site broad signaling pathway screen, we found that in conditioned neurons with high regenerative capacity, decreased glycogen synthase kinase 3β (GSK3β) activity and increased microtubule growth speed in the growth cone were present. To investigate the importance of GSK3β regulation during axonal regeneration in vivo, we used three genetic mouse models with high, intermediate or no GSK3β activity in neurons. Following spinal cord injury, reduced GSK3β levels or complete neuronal deletion of GSK3β led to increased growth cone microtubule growth speed and promoted axon regeneration. While several microtubule-interacting proteins are GSK3β substrates, phospho-mimetic collapsin response mediator protein 2 (T/D-CRMP-2) was sufficient to decrease microtubule growth speed and neurite outgrowth of conditioned neurons and of GSK3β-depleted neurons, prevailing over the effect of decreased levels of phosphorylated microtubule-associated protein 1B (MAP1B) and through a mechanism unrelated to decreased levels of phosphorylated cytoplasmic linker associated protein 2 (CLASP2). In addition, phospho-resistant T/A-CRMP-2 counteracted the inhibitory myelin effect on neurite growth, further supporting the GSK3β-CRMP-2 relevance during axon regeneration.ConclusionsOur work shows that increased microtubule growth speed in the growth cone is present in conditions of increased axonal growth, and is achieved following inactivation of the GSK3β-CRMP-2 pathway, enhancing axon regeneration through the glial scar. In this context, our results support that a precise control of microtubule dynamics, specifically in the growth cone, is required to optimize axon regrowth.

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“…[32][33][34] Furthermore, in primary cortical neurons, RGMa exerts the suppressive function by phosphorylating collapsin response mediator protein-2 (CRMP-2) via both Rho-kinase and GSK-3b signaling pathways. 35 Also, in cerebellar granule neurons, RGMa inhibits neurite outgrowth via myosin IIA, a downstream effector of Rho kinase. 36 However, RGMa also functions as a novel coreceptor of bone morphogenetic proteins (BMPs), which belong to the superfamily of transforming growth factor beta (TGF-b).…”

Section: Discussionmentioning

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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CRMP-2 Is Involved in Axon Growth Inhibition Induced by RGMa In Vitro and In Vivo

Cited by 28 publications

References 32 publications

Changes of fractional anisotropy and RGMa in crossed cerebellar diaschisis induced by middle cerebral artery occlusion

Changes of fractional anisotropy and RGMa in crossed cerebellar diaschisis induced by middle cerebral artery occlusion

Neuronal deletion of GSK3β increases microtubule speed in the growth cone and enhances axon regeneration via CRMP-2 and independently of MAP1B and CLASP2

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

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