Activated RHOA and peripheral axon regeneration

Cheng, Chu; Webber, Christine A.; Wang, J.; Xu, Yanhong; Martinez, José A.; Liu, W.Q.; McDonald, David S.; Guo, Gui Fang; Nguyen, Minh Dang; Zochodne, Douglas W.

doi:10.1016/j.expneurol.2008.04.023

Cited by 78 publications

(69 citation statements)

References 41 publications

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“…Activation of RhoA has been described in experimental models of sciatic nerve injury (38) and after exposure to CNS myelin (37). Our studies demonstrate that RhoA signaling is also a key regulator of Nogo-A expression in sensory neurons.…”

Section: Discussionsupporting

confidence: 63%

“…Inhibition of RhoA and its downstream kinase ROCK have been found to enhance neurite growth (37,38). To explore the mechanism underlying up-regulation of neuronal Nogo-A by CNS myelin, we used the cell-permeable bacterial ADP-ribosyltransferase C3, which inhibits RhoA activity by promoting Rho-GDI complex formation and decreasing binding of RhoA to the membrane (39).…”

Section: Neuronal Nogo-a Is Increased Following Axonal Injury In Vivomentioning

confidence: 99%

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Soluble Nogo Receptor Down-regulates Expression of Neuronal Nogo-A to Enhance Axonal Regeneration

Peng

Zhou

et al. 2010

Journal of Biological Chemistry

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Nogo-A, a member of the reticulon family, is present in neurons and oligodendrocytes. Nogo-A in central nervous system (CNS) myelin prevents axonal regeneration through interaction with Nogo receptor 1, but the function of Nogo-A in neurons is less known. We found that after axonal injury, Nogo-A is increased in dorsal root ganglion (DRG) neurons unable to regenerate following a dorsal root injury or a sciatic nerve ligation-cut injury and that exposure in vitro to CNS myelin dramatically enhanced neuronal Nogo-A mRNA and protein through activation of RhoA while inhibiting neurite growth. Knocking down neuronal Nogo-A by small interfering RNA results in a marked increase of neurite outgrowth. We constructed a nonreplicating herpes simplex virus vector (QHNgSR) to express a truncated soluble fragment of Nogo receptor 1 (NgSR). NgSR released from QHNgSR prevented myelin inhibition of neurite extension by hippocampal and DRG neurons in vitro. NgSR prevents RhoA activation by myelin and decreases neuronal Nogo-A. Subcutaneous inoculation of QHNgSR to transduce DRG neurons resulted in improved regeneration of myelinated fibers in both the dorsal root and the spinal dorsal root entry zone, with concomitant improvement in sensory behavior. The results indicate that neuronal Nogo-A is an important intermediate in neurite growth dynamics and its expression is regulated by signals related to axonal injury and regeneration, that CNS myelin appears to activate signaling events that mimic axonal injury, and that NgSR released from QHNgSR may be used to improve recovery after injury.

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Section: Discussionsupporting

confidence: 63%

Section: Neuronal Nogo-a Is Increased Following Axonal Injury In Vivomentioning

confidence: 99%

Soluble Nogo Receptor Down-regulates Expression of Neuronal Nogo-A to Enhance Axonal Regeneration

Peng

Zhou

et al. 2010

Journal of Biological Chemistry

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“…A transected sciatic nerve with a 3-5 mm gap between the proximal and distal stumps was bridged by a silicone regeneration chamber (conduit) connected by a T junction to a subcutaneous access port as previously described (McDonald and Zochodne, 2003). In prior work, inhibition of SC proliferation, RHOA inactivation, and NGF administration have each altered outgrowth using this assay (Kemp et al, 2007;Cheng et al, 2008). In vivo pharmacological inhibition of PTEN using bpV(pic) resulted in an increase in the number and length of outgrowing axons from the proximal stump of the transected nerve into the regenerative bridge (Fig.…”

Section: In Vivo Inhibition Of Pten Increases Axonal Outgrowthmentioning

confidence: 90%

PTEN Inhibition to Facilitate Intrinsic Regenerative Outgrowth of Adult Peripheral Axons

Christie¹,

Webber²,

Martinez³

et al. 2010

Journal of Neuroscience

297

283

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In vivo regeneration of peripheral neurons is constrained and rarely complete, and unfortunately patients with major nerve trunk transections experience only limited recovery. Intracellular inhibition of neuronal growth signals may be among these constraints. In this work, we investigated the role of PTEN (phosphatase and tensin homolog deleted on chromosome 10) during regeneration of peripheral neurons in adult Sprague Dawley rats. PTEN inhibits phosphoinositide 3-kinase (PI3-K)/Akt signaling, a common and central outgrowth and survival pathway downstream of neuronal growth factors. While PI3-K and Akt outgrowth signals were expressed and activated within adult peripheral neurons during regeneration, PTEN was similarly expressed and poised to inhibit their support. PTEN was expressed in neuron perikaryal cytoplasm, nuclei, regenerating axons, and Schwann cells. Adult sensory neurons in vitro responded to both graded pharmacological inhibition of PTEN and its mRNA knockdown using siRNA. Both approaches were associated with robust rises in the plasticity of neurite outgrowth that were independent of the mTOR (mammalian target of rapamycin) pathway. Importantly, this accelerated outgrowth was in addition to the increased outgrowth generated in neurons that had undergone a preconditioning lesion. Moreover, following severe nerve transection injuries, local pharmacological inhibition of PTEN or siRNA knockdown of PTEN at the injury site accelerated axon outgrowth in vivo. The findings indicated a remarkable impact on peripheral neuron plasticity through PTEN inhibition, even within a complex regenerative milieu. Overall, these findings identify a novel route to propagate intrinsic regeneration pathways within axons to benefit nerve repair.

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“…The intrinsic growth state of neurons is potentiated by the upregulation of neurotrophins; in contrast, regenerative roadblocks such as PTEN diminish these intrinsic growth capacities (Cheng et al, 2008;Christie et al, 2010;Park et al, 2010). The impact of ES on the expression of this inhibitory molecule is however, unknown.…”

Section: Es-associated Upregulation Of the Pi3-k Pathway In Adult Senmentioning

confidence: 99%

Peripheral neuron plasticity is enhanced by brief electrical stimulation and overrides attenuated regrowth in experimental diabetes

Singh

Krishnan

Micu

et al. 2015

Neurobiology of Disease

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Activated RHOA and peripheral axon regeneration

Cited by 78 publications

References 41 publications

Soluble Nogo Receptor Down-regulates Expression of Neuronal Nogo-A to Enhance Axonal Regeneration

Soluble Nogo Receptor Down-regulates Expression of Neuronal Nogo-A to Enhance Axonal Regeneration

PTEN Inhibition to Facilitate Intrinsic Regenerative Outgrowth of Adult Peripheral Axons

Peripheral neuron plasticity is enhanced by brief electrical stimulation and overrides attenuated regrowth in experimental diabetes

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