Monnier, P. P., Sierra, A., Schwab, J. M., Henke-Fahle, S. & Mueller, B. K. The Rho/ROCK pathway mediates neurite growth-inhibitory activity associated with the chondroitin sulfate proteoglycans of the CNS glial scar. Mol. Cell Neurosci. 22, 319-330

Migragen AG, Spemannstrasse 34, D-72076 Tübingen, Germany.
Molecular and Cellular Neuroscience (Impact Factor: 3.84). 04/2003; 22(3):319-30. DOI: 10.1016/S1044-7431(02)00035-0
Source: PubMed


Axons fail to regenerate in the central nervous system after injury. Chondroitin sulfate proteoglycans (CSPG) expressed in the scar significantly contribute to the nonpermissive properties of the central nervous system environment. To examine the inhibitory activity of a CSPG mixture on retina ganglion cell (RGC) axon growth, we employed both a stripe assay and a nerve fiber outgrowth assay. We show that the inhibition exerted by CSPGs in vitro can be blocked by application of either C3 transferase, a specific inhibitor of the Rho GTPase, or Y27632, a specific inhibitor of the Rho kinase. These results demonstrate that CSPG-associated inhibition of neurite outgrowth is mediated by the Rho/ROCK signaling pathway. Consistent with these results, we found that retina ganglion cell axon growth on glial scar tissue was enhanced in the presence of C3 transferase and Y27632, respectively. In addition, we show that the recently identified inhibitory CSPG Te38 is upregulated in the lesioned spinal cord.

Download full-text


Available from: Jan M Schwab, Mar 12, 2015
  • Source
    • "Similar to these in vitro findings, blockage of the Rho/ROCK pathway in vivo has shown similar growth promoting effect on axonal regeneration following CNS injury. Inhibition of the Rho/ROCK pathway with either C3 exoenzyme or Y-27632 promotes axonal regeneration following SCI (Chan et al., 2005; Dergham et al., 2002; Fournier et al., 2003; Monnier et al., 2003; Ramer et al., 2004). Interestingly, RhoA inhibition with C3 exoenzyme has been shown to reduce cell death following SCI in rodents demonstrating the potential neuroprotective benefits of RhoA inhibition (Dubreuil et al., 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chondroitin Sulfate Proteoglycans (CSPGs) are a major component of the extracellular matrix in the central nervous system (CNS) and play critical role in the development and pathophysiology of the brain and spinal cord. Developmentally, CSPGs provide guidance cues for growth cones and contribute to the formation of neuronal boundaries in the developing CNS. Their presence in perineuronal nets plays a crucial role in the maturation of synapses and closure of critical periods by limiting synaptic plasticity. Following injury to the CNS, CSPGs are dramatically upregulated by reactive glia which form a glial scar around the lesion site. Increased level of CSPGs is a hallmark of all CNS injuries and has been shown to limit axonal plasticity, regeneration, remyelination, and conduction after injury. Additionally, CSPGs create a non-permissive milieu for cell replacement activities by limiting cell migration, survival and differentiation. Mounting evidence is currently shedding light on the potential benefits of manipulating CSPGs in combination with other therapeutic strategies to promote spinal cord repair and regeneration. Moreover, the recent discovery of multiple receptors for CSPGs provides new therapeutic targets for targeted interventions in blocking the inhibitory properties of CSPGs following injury. Here, we will provide an in depth discussion on the impact of CSPGs in normal and pathological CNS. We will also review the recent preclinical therapies that have been developed to target CSPGs in the injured CNS. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Apr 2015 · Experimental Neurology
  • Source
    • "The inhibitory activity of MAG and other myelin-associated inhibitors appears to require the Rho/ROCK pathway (Lehmann et al., 1999; Vinson et al., 2001). Other inhibitors such as CSPGs and semaphorin and ephrin members also activate the Rho/ ROCK pathway (Monnier et al., 2003; Sivasankaran et al., 2004; Kubo et al., 2008). Moreover, inactivating Rho or ROCK improves neurite outgrowth of primary neurons on inhibitor substrates in vitro and axon regeneration in vivo (Dergham et al., 2002; Winton et al., 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chondroitin sulfate proteoglycan (CSPG) inhibits neurite outgrowth of various neuronal cell types, and CSPG-associated inhibition of neurite outgrowth is mediated by the Rho/ROCK pathway. Mesenchymal stromal/stem cells (MSCs) have the potential to differentiate into neuron-like cells under specific conditions and have been shown to differentiate into neuron-like cells by co-treatment with the ROCK inhibitor Y27632 and the hypoxia condition mimicking agent CoCl2. In this study, we addressed the hypothesis that a ROCK inhibitor might be beneficial to regenerate neurons during stem cell therapy by preventing transplanted MSCs from inhibition by CSPG in damaged tissues. Indeed, dose-dependent inhibition by CSPG pretreatment was observed during morphological changes of Wharton's jelly-derived MSCs (WJ-MSCs) induced by Y27632 alone. The formation of neurite-like structures was significantly inhibited when WJ-MSCs were pre-treated with CSPG before induction under Y27632 plus CoCl2 conditions, and pretreatment with a protein kinase C inhibitor reversed such inhibition. However, CSPG treatment resulted in no significant inhibition of the WJ-MSC morphological changes into neuron-like cells after initiating induction by Y27632 plus CoCl2. No marked changes were detected in expression levels of neuronal markers induced by Y27632 plus CoCl2 upon CSPG treatment. CSPG also blocked the morphological changes of human bone marrow-derived MSCs into neuron-like cells under other neuronal induction condition without the ROCK inhibitor, and Y27632 pre-treatment blocked the inhibitory effect of CSPG. These results suggest that a ROCK inhibitor can be efficiently used in stem cell therapy for neuronal induction by avoiding hindrance from CSPG.
    Full-text · Article · Nov 2013 · Biomolecules and Therapeutics
  • Source
    • "2A–C) (Ahmed et al., 2009; Sengottuvel et al., 2011). In contrast to the ROCK inhibitor Y27632, which is known to block the intracellular inhibitory signaling cascade (Dergham et al., 2002; Monnier et al., 2003), CXCL12 could not overcome neurocan mediated growth inhibition and clearly remained below levels reached on laminin (Figs. 2A, B). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mature retinal ganglion cells (RGCs) do not normally regenerate injured axons, but undergo apoptosis soon after axotomy. Besides the insufficient intrinsic capability of mature neurons to regrow axons inhibitory molecules located in myelin of the central nervous system as well as the forming glial scar at the site of injury strongly limit axon regeneration. Nevertheless, RGCs can be transformed into a regenerative state upon lens injury, enabling these neurons to grow axons into the injured optic nerve. The outcome of lens injury stimulated regeneration is, however, still limited by the inhibitory extracellular environment. Here, we report that the chemokine CXCL12 moderately stimulates neurite growth of mature RGCs on laminin in culture and, in contrast to CNTF, exerts potent disinhibitory effects towards myelin. Consistently, co-treatment of RGCs with CXCL12 facilitated CNTF stimulated neurite growth of RGCs on myelin. Mature RGCs express CXCR4, the cognate CXCL12 receptor. Furthermore the neurite growth promoting and disinhibitory effects of CXCL12 were abrogated by a specific CXCR4 antagonist and inhibition of the PI3K/AKT/mTOR-, but not the JAK/STAT3- pathway. In vivo, intravitreal application of CXCL12 sustained mTOR activity in RGCs upon optic nerve injury and moderately stimulated axon regeneration in the optic nerve without affecting the survival of RGCs. Importantly, intravitreal application of CXCL12 also significantly increased lens injury triggered axon regeneration in vivo. These data suggest that the disinhibitory effect of CXCL12 towards myelin may be a useful feature to facilitate optic nerve regeneration, particularly in combination with other axon growth stimulatory treatments.
    Full-text · Article · Apr 2013 · Neurobiology of Disease
Show more