Rapamycin-Resistant mTOR Activity Is Required for Sensory Axon Regeneration Induced by a Conditioning Lesion

Chen, Weitao; Lü, Na; Ding, Yi; Wang, Yuan; Chan, Leung Ting; Wang, Xu; Gao, Xin; Jiang, Siqi; Liu, Kai

doi:10.1523/eneuro.0358-16.2016

Cited by 46 publications

(36 citation statements)

References 49 publications

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“…As a regulator of PI3K/Akt pathways, RICTOR is a key component of mTORC2 and is clearly involved in cell proliferation and repair. In agreement with this concept, the deletion of Rictor or mTORC2 inhibited the sensory-axonal regeneration in mice after dorsal root ganglion injury 51 .…”

Section: Discussionsupporting

confidence: 56%

Novel RvD6 stereoisomer induces corneal nerve regeneration and wound healing post-injury by modulating trigeminal transcriptomic signature

Pham

Kakazu

et al. 2020

Sci Rep

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The high-density corneal innervation plays a pivotal role in sustaining the integrity of the ocular surface. We have previously demonstrated that pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA) promotes corneal nerve regeneration; here, we report the mechanism involved and the discovery of a stereospecific Resolvin D6-isomer (RvD6si) that drives the process. RvD6si promotes corneal wound healing and functional recovery by restoring corneal innervation after injury. RvD6si applied to the eye surface elicits a specific transcriptome signature in the trigeminal ganglion (TG) that includes Rictor, the rapamycin-insensitive complex-2 of mTOR (mTORC2), and genes involved in axon growth, whereas genes related to neuropathic pain are decreased. As a result, attenuation of ocular neuropathic pain and dry eye will take place. Thus, RvD6si opens up new therapeutic avenues for pathologies that affect corneal innervation.model of refractive surgery 20 . Herein, we report the discovery of a novel lipid mediator that is part of the signaling mechanism exerted by PEDF + DHA on the ocular surface. Furthermore, we uncovered that the TG genes sense corneal injury and respond to corneal stereospecific Resolvin D6-isomer (RvD6si) treatment with a specific transcriptomic signature. We demonstrate that the topical application of RvD6si is cornea protective, revealing novel mechanisms and potential therapeutic avenues for dry eye and ocular neuropathic pain. ResultsIdentification of novel RvD6si in mouse tears. The biological activities of PEDF + DHA have been revealed previously by our laboratory [20][21][22][23][24] . A mechanistic link of PEDF + DHA action on corneal nerve regeneration has been uncovered with the activation of the iPLA2ζ and the increased expression of the neurotrophic factors, brain-derived growth factor (BDNF) and nerve growth factor (NGF), and the axon growth guidance semaphorin 7a (Sema7A) released in tears 25 . To define which docosanoids are produced after the release of DHA by PEDF activation, mouse corneas were injured and treated, tears collected, and lipids extracted and analyzed by LC-MS/MS (Fig. 1A). The total ion chromatogram (TIC) of 359 m/z represented all di-hydroxy DHA isomers in tears after 4 h of treatment, and three peaks were well defined with retention times (RT) 8.20, 8.74, and 9.20 min (Fig. 1B). The internal standard LTB 4 -d4 (green) eluted at 8.25 min. We focused on the peak eluted at 8.20 min (Peak 1) that displays a parent ion 359 m/z upon full fragmentation, showing at least 6 matched product ions (daughter ions) compared to the RvD6 standard (Fig. 1C) with two hydroxy-groups at Carbon number 4 and 17 (Fig. 1D). When Peak 1 was co-injected with RvD6 at the same concentration, Peak 1 eluted 0.27 min earlier than RvD6 at 6 major multiple reaction monitoring (MRM) channels 359 −> 297, 279, 239, 199, 159, and 101 (Fig. 1E). The UV spectra for Peak 1 and RvD6 showed maxima absorbance (λ max ) at 238 nm, revealing that both compounds have a conjugated diene structure (...

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Section: Discussionsupporting

confidence: 56%

Novel RvD6 stereoisomer induces corneal nerve regeneration and wound healing post-injury by modulating trigeminal transcriptomic signature

Pham

Kakazu

et al. 2020

Sci Rep

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“…This phenotype is driven by JUN (Fontana et al, ), which can be regulated by O ‐GlcNAcylation (Kim et al, ). Another possibility is that DRG neurons have a reduced intrinsic capacity to regenerate in diabetic mice, since modulating mTOR in DRG neurons affects axon regeneration speeds (Carlin, Halevi, Ewan, Moore, & Cavalli, ; Chen et al, ; Singh et al, ). Together, these data demonstrate that insulin/IGF1 signaling regulate remyelination but not SC dedifferentiation or axon regeneration.…”

Section: Discussionmentioning

confidence: 99%

“…This phenotype is driven by JUN (Fontana et al, 2012), which can be regulated by O-GlcNAcylation . Another possibility is that DRG neurons have a reduced intrinsic capacity to regenerate in diabetic mice, since modulating mTOR in DRG neurons affects axon regeneration speeds (Carlin, Halevi, Ewan, Moore, & Cavalli, 2019;Chen et al, 2016;Singh et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Disrupting insulin signaling in Schwann cells impairs myelination and induces a sensory neuropathy

Hackett

Strickland

Milbrandt

2019

Glia

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Although diabetic mice have been studied for decades, little is known about the cell type specific contributions to diabetic neuropathy (DN). Schwann cells (SCs) myelinate and provide trophic support to peripheral nervous system axons. Altered SC metabolism leads to myelin defects, which can be seen both in inherited and DNs. How SC metabolism is altered in DN is not fully understood, but it is clear that insulin resistance underlies impaired lipid metabolism in many cell types throughout the body via the phosphoinositide 3‐kinase/protein kinase b (PKB)/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Here, we created an insulin resistant SC by deleting both insulin receptor (INSR) and insulin‐like growth factor receptor 1 (IGF1R), to determine the role of this signaling pathway in development and response to injury in order to understand SC defects in DN. We found that myelin is thinner throughout development and adulthood in INSR/IGF1R Schwann cell specific knock out mice. The nerves of these mutant mice had reduced expression of key genes that mediate fatty acid and cholesterol synthesis due to reduced mTOR–sterol regulatory element‐binding protein signaling. In adulthood, these mice show sensory neuropathy phenotypes reminiscent of diabetic mice. Altogether, these data suggest that SCs may play an important role in DN and targeting their metabolism could lead to new therapies for DN.

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“…However, both the upstream and downstream mechanisms involved in mTOR function in axon regeneration are not well understood. Crosstalk between mTOR and STAT3 signalling pathways 97 , as well as negative feedback by the mTOR downstream target ribosomal protein S6 kinase-β1 (S6K1) 98 , suggest that a deeper understanding of this master regulator of axon growth is needed.…”

Section: Injury Signallingmentioning

confidence: 99%

Intrinsic mechanisms of neuronal axon regeneration

2018

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Permanent disabilities following CNS injuries result from the failure of injured axons to regenerate and rebuild functional connections with their original targets. By contrast, injury to peripheral nerves is followed by robust regeneration, which can lead to recovery of sensory and motor functions. This regenerative response requires the induction of widespread transcriptional and epigenetic changes in injured neurons. Considerable progress has been made in recent years in understanding how peripheral axon injury elicits these widespread changes through the coordinated actions of transcription factors, epigenetic modifiers and, to a lesser extent, microRNAs. Although many questions remain about the interplay between these mechanisms, these new findings provide important insights into the pivotal role of coordinated gene expression and chromatin remodelling in the neuronal response to injury.

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Rapamycin-Resistant mTOR Activity Is Required for Sensory Axon Regeneration Induced by a Conditioning Lesion

Cited by 46 publications

References 49 publications

Novel RvD6 stereoisomer induces corneal nerve regeneration and wound healing post-injury by modulating trigeminal transcriptomic signature

Novel RvD6 stereoisomer induces corneal nerve regeneration and wound healing post-injury by modulating trigeminal transcriptomic signature

Disrupting insulin signaling in Schwann cells impairs myelination and induces a sensory neuropathy

Intrinsic mechanisms of neuronal axon regeneration

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