Activation of Rho in the injured axons following spinal cord injury

Madura, Tomas; Yamashita, Toshio; Kubo, Tateki; Fujitani, Masashi; Hosokawa, Ko; Tohyama, Masaya

doi:10.1038/sj.embor.7400117

Cited by 88 publications

(73 citation statements)

References 18 publications

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“…RhoA activation is critical in the pathway by which MAIs inhibit neurite outgrowth in neurons and neuron-like cells (Kozma et al, 1997;Kuhn et al, 1999;Yamashita et al, 2002;Madura et al, 2004). Blocking RhoA activation promotes neurite outgrowth (Jalink et al, 1994;Jeon et al, 2012), even in cells plated on inhibitory substrata (Niederöst et al, 2002;Fu et al, 2007;Tan et al, 2007).…”

Section: Binding Of Mag To Lrp1 Recruits P75ntr and Activates Rhoamentioning

confidence: 99%

LDL receptor-related protein-1 is a sialic-acid-independent receptor for myelin-associated glycoprotein that functions in neurite outgrowth inhibition by MAG and CNS myelin

Stiles

Dickendesher

Gaultier

et al. 2013

Journal of Cell Science

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SummaryIn the injured adult mammalian central nervous system (CNS), products are generated that inhibit neuronal sprouting and regeneration. In recent years, most attention has focused on the myelin-associated inhibitory proteins (MAIs) Nogo-A, OMgp, and myelin-associated glycoprotein (MAG). Binding of MAIs to neuronal cell-surface receptors leads to activation of RhoA, growth cone collapse, and neurite outgrowth inhibition. In the present study, we identify low-density lipoprotein (LDL) receptor-related protein-1 (LRP1) as a high-affinity, endocytic receptor for MAG. In contrast with previously identified MAG receptors, binding of MAG to LRP1 occurs independently of terminal sialic acids. In primary neurons, functional inactivation of LRP1 with receptor-associated protein, depletion by RNA interference (RNAi) knock-down, or LRP1 gene deletion is sufficient to significantly reverse MAG and myelin-mediated inhibition of neurite outgrowth. Similar results are observed when LRP1 is antagonized in PC12 and N2a cells. By contrast, inhibiting LRP1 does not attenuate inhibition of neurite outgrowth caused by chondroitin sulfate proteoglycans. Mechanistic studies in N2a cells showed that LRP1 and p75NTR associate in a MAG-dependent manner and that MAG-mediated activation of RhoA may involve both LRP1 and p75NTR. LRP1 derivatives that include the complement-like repeat clusters CII and CIV bind MAG and other MAIs. When CII and CIV were expressed as Fc-fusion proteins, these proteins, purified full-length LRP1 and shed LRP1 all attenuated the inhibition of neurite outgrowth caused by MAG and CNS myelin in primary neurons. Collectively, our studies identify LRP1 as a novel MAG receptor that functions in neurite outgrowth inhibition.

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Section: Binding Of Mag To Lrp1 Recruits P75ntr and Activates Rhoamentioning

confidence: 99%

LDL receptor-related protein-1 is a sialic-acid-independent receptor for myelin-associated glycoprotein that functions in neurite outgrowth inhibition by MAG and CNS myelin

Stiles

Dickendesher

Gaultier

et al. 2013

Journal of Cell Science

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“…RhoA activation leads to actin depolymerization and growth cone collapse (Jalink et al, 1994;Gallo and Letourneau, 2004). After SCI, RhoA is highly activated at the lesion site (Dubreuil et al, 2003;Madura et al, 2004), and antagonism of RhoA or its downstream effector Rho-kinase (ROCK) enhances both regeneration and recovery after SCI (Dergham et al, 2002;Fournier et al, 2003). Recent data indicate that Rho or ROCK inhibitors also prevent pain that normally develops as a consequence of sciatic nerve injury, possibly by preventing injury-induced upregulation of the protein kinase C ␥-isoform (PKC␥) in the dorsal horn (Inoue et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Rho-Kinase Inhibition Enhances Axonal Plasticity and Attenuates Cold Hyperalgesia after Dorsal Rhizotomy

Ramer

Borisoff²,

Ramer³

2004

J. Neurosci.

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Dorsal rhizotomy results in primary deafferentation of the dorsal horn with concomitant sprouting of spared intraspinal monoaminergic axons. Because descending monoaminergic systems are thought to mitigate nociceptive transmission from the periphery and because dorsal rhizotomy can result in neuropathic pain, we sought to determine whether the rhizotomy-induced sprouting response could be further augmented. Because myelin-derived molecules mask endogenous plasticity of CNS axons and because myelin-inhibitory signaling occurs through the Rho-GTPase pathway, we inhibited Rho-pathway signaling after cervical dorsal rhizotomy in rats. An increase in the density of serotonergic-and tyrosine hydroxylase-positive fibers was seen in the dorsal horn 1 week after septuple rhizotomy, and axon density continued to increase for at least 1 month. One week after septuple rhizotomy, administration of intrathecal Y-27632, an antagonist of Rho-kinase (ROCK), increased the density of both fiber types over vehicle-treated controls. To examine behavioral effects of both cervical rhizotomy and ROCK inhibition, we examined responses to evoked pain: mechanical and thermal allodynia and cold hyperalgesia in the forepaw were examined after single, double, and quadruple rhizotomies of dorsal roots of the brachial plexus. The most notable behavioral outcome was the development of cold hyperalgesia in the affected forepaw after rhizotomies of the C7 and C8 dorsal roots. Application of Y-27632 both attenuated cold hyperalgesia and induced monoaminergic plasticity after C7/8 rhizotomy. Thus, inhibition of Rho-pathway signaling both promoted the sprouting of intact supraspinal monoaminergic fibers and alleviated pain after dorsal rhizotomy.

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“…Rho GTPases are involved in the critical morphological changes that occur during development including neurite outgrowth, dendritic arbor maturation, and axon outgrowth (Davies, 2000;Schmidt and Hall, 2002) . Rho activation has been shown to correlate with spinal cord injury in a number of studies (Dubreuil et al, 2006;Madura et al, 2004). Inhibition of Rho after neuronal injury encourages axonal outgrowth and regeneration of affected neurons (Ellezam et al, 2002;Madura et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants

et al. 2008

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Many chemotherapy drugs are known to cause significant clinical neurotoxicity, which can result in the early cessation of treatment. To identify and develop more effective means of neuroprotection it is important to understand the toxicity of these drugs at the molecular and cellular levels. In the present study, we examine the effects of paclitaxel (taxol), cisplatin, and methotrexate on primary rat neurons including hippocampal, cortical, and dorsal horn/dorsal root ganglion neuronal cultures. We found that all of these anti-cancer drugs induce substantial neurotoxicity evidenced by neurite degeneration. The neurons are capable of recovering after treatment withdrawal, but taxol exerts a biphasic effect that results in the collapse of processes days after treatment is withdrawn. After cisplatin and methotrexate treatment, we observed the degeneration of neuronal processes including the reduction of dendritic branching, length, and altered growth cone formation, indicating an abnormal arrangement of the actin cytoskeleton consistent with the involvement of Rho family small GTPases. Inhibiting RhoA downstream effector p160 ROCK /Rho kinase using Y-27632, or activating p75 neurotrophin receptor (p75 NTR ) using non-peptide mimetic LM11A-31, were able to reverse the degeneration caused by cisplatin and methotrexate. Therefore, the neurotoxicity resulting from exposure to the anti-cancer drugs cisplatin and methotrexate can be alleviated by inhibiting Rho signaling pathway.

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Activation of Rho in the injured axons following spinal cord injury

Cited by 88 publications

References 18 publications

LDL receptor-related protein-1 is a sialic-acid-independent receptor for myelin-associated glycoprotein that functions in neurite outgrowth inhibition by MAG and CNS myelin

LDL receptor-related protein-1 is a sialic-acid-independent receptor for myelin-associated glycoprotein that functions in neurite outgrowth inhibition by MAG and CNS myelin

Rho-Kinase Inhibition Enhances Axonal Plasticity and Attenuates Cold Hyperalgesia after Dorsal Rhizotomy

Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants

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