Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system

Dubreuil, Catherine; Winton, Matthew J.; McKerracher, Lisa

doi:10.1083/jcb.200301080

Cited by 366 publications

(333 citation statements)

References 62 publications

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“…However, in Schwann cells, endogenous RhoA was activated after stimulation with BDNF, whereas knockdown of p75 NTR inhibited this activation (Yamauchi et al, 2004). In spinal cord injury (SCI) model, blocking activation of Rho after SCI protects cells from p75 NTR -dependent apoptosis (Dubreuil et al, 2003). In our experiments, p75 NTR mimetic LM11A-31 stimulation led to inhibition of Rho GTPase in anti-cancer drug treated cells, supporting the notion that p75 NTR effects are context dependent.…”

Section: Discussionsupporting

confidence: 78%

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withdrawal, but taxol exerts a biphasic effect that results in the collapse of processes days after treatment is withdrawn.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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Section: Discussionsupporting

confidence: 78%

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

et al. 2008

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“…Moreover, the activation of Rho-A by myelin Nogo-A could be damaging for neurons after injury; blocking Rho-A activation after spinal cord injury protected the cells from p75 NTR -dependent apoptosis. 55 Similarly, the increase of retinal ganglion cell survival in Cnp-Cre þ / À xRtn4 flox/flox mice could be due to the reduction of Rho-A activation that we observed in axotomized retinae.…”

Section: Moreover Inflammation-inducing Agents Such As Zymosan or Pamentioning

confidence: 56%

Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve

et al. 2014

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Nogo-A is a well-known myelin-enriched inhibitory protein for axonal growth and regeneration in the central nervous system (CNS). Besides oligodendrocytes, our previous data revealed that Nogo-A is also expressed in subpopulations of neurons including retinal ganglion cells, in which it can have a positive role in the neuronal growth response after injury, through an unclear mechanism. In the present study, we analyzed the opposite roles of glial versus neuronal Nogo-A in the injured visual system. To this aim, we created oligodendrocyte (Cnp-Cre þ / À xRtn4/Nogo-A flox/flox ) and neuron-specific (Thy1-Cre tg þ xRtn4 flox/flox ) conditional Nogo-A knock-out (KO) mouse lines. Following complete intraorbital optic nerve crush, both spontaneous and inflammation-mediated axonal outgrowth was increased in the optic nerves of the glia-specific Nogo-A KO mice. In contrast, neuron-specific deletion of Nogo-A in a KO mouse line or after acute gene recombination in retinal ganglion cells mediated by adeno-associated virus serotype 2.Cre virus injection in Rtn4 flox/flox animals decreased axon sprouting in the injured optic nerve. These results therefore show that selective ablation of Nogo-A in oligodendrocytes and myelin in the optic nerve is more effective at enhancing regrowth of injured axons than what has previously been observed in conventional, complete Nogo-A KO mice. Our data also suggest that neuronal Nogo-A in retinal ganglion cells could participate in enhancing axonal sprouting, possibly by cis-interaction with Nogo receptors at the cell membrane that may counteract trans-Nogo-A signaling. We propose that inactivating Nogo-A in glia while preserving neuronal Nogo-A expression may be a successful strategy to promote axonal regeneration in the CNS.

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“…This signal may counteract the Rap1 signal. It was reported that the application of the Rho antagonist C3-05 reduced the number of TUNEL-positive cells by B50% in both rats and mice with spinal cord injuries, 25 suggesting that Rho may be the signal responsible for cell death. Our preliminary data demonstrate that the application of Y-27632 -a Rho-kinase inhibitor -reduced the number of TUNEL-positive CGNs that were pretreated with TAT-Rap1 DN and then incubated with MAG-Fc (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Rap1 is involved in the signal transduction of myelin-associated glycoprotein

et al. 2007

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Myelin-associated glycoprotein (MAG) is a well-characterized axon growth inhibitor in the adult vertebrate nervous system. Several signals that play roles in inhibiting axon growth have been identified. Here, we report that soluble MAG induces activation of Rap1 in postnatal cerebellar granule neurons (CGNs) and dorsal root ganglion (DRG) neurons. The p75 receptor associates with activated Rap1 and is internalized in response to MAG. After MAG is applied to the distal axons of the sciatic nerves, the activated Rap1, internalized p75 receptor, and MAG are retrogradely trafficked via axons to the cell bodies of the DRG neurons. Rap1 activity is required for survival of the DRG neurons as well as CGNs when treated with MAG. Myelin-associated glycoprotein (MAG) is a member of the I-type lectin subgroup of the immunoglobulin (Ig) gene superfamily and is expressed exclusively by myelinating cells where it is enriched in the adaxonal membrane of the myelin internode. MAG inhibits neurite outgrowth from the adult dorsal root ganglion (DRG) and the postnatal ages of the cerebellar, retinal, spinal, hippocampal, and superior cervical ganglion neurons. 1,2 To date, two additional neurite growth inhibitors that are expressed by oligodendrocytes and myelinated fiber tracts have been identified. 3 These are Nogo and oligodendrocyte-myelin glycoprotein. All these proteins act on neurons through the Nogo receptor complex. This is a trimolecular complex comprising the Nogo receptor, Lingo-1, and p75/Troy. 4 A key intracellular effector for neurite growth inhibitory signaling by myelin was previously shown to be the small guanine nucleoside triphosphatase, RhoA. In its active GTP-bound form, RhoA rigidifies the actin cytoskeleton, thereby inhibiting axon elongation and mediating growth cone collapse. RhoA is activated by these proteins through a p75-dependent mechanism, thus inhibiting neurite outgrowth from the postnatal sensory neurons and cerebellar neurons. 5,6 It was also demonstrated that conventional protein kinase C (PKC), including PKC-a, -b, and -g, was activated by the neurite growth inhibitory proteins, and the inhibition of conventional PKC eliminated the effect of these proteins on neurite outgrowth. 7,8 In addition, phosphorylation of the epidermal growth factor (EGF) receptor is triggered by these myelin-derived inhibitors and is necessary for the inhibitory effect. 9 These multiple signals are responsible for the effects of the myelin-derived inhibitors at least in vitro.In addition to the role of MAG in axon regeneration, experiments with MAG-deficient mice implicate this protein in regulating axonal caliber and the levels of neurofilament spacing in mature myelinated fibers. 10 MAG is suggested to modulate the maturation and viability of myelinated axons. These findings suggest the diverse functions of MAG in the nervous system.In the course of identifying signals downstream of MAG, we found that Rap1 is activated in response to soluble MAG. Rap1 is a member of the Ras family of small guanine nucleotidebinding ...

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Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system

Cited by 366 publications

References 62 publications

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

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

Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve

Rap1 is involved in the signal transduction of myelin-associated glycoprotein

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