Axotomized mouse retinal ganglion cells containing melanopsin show enhanced survival, but not enhanced axon regrowth into a peripheral nerve graft

Robinson, Grant A.; Madison, Roger D.

doi:10.1016/j.visres.2004.06.010

Cited by 96 publications

(84 citation statements)

References 30 publications

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“…We showed that Opn4-GFP + axons also did not regenerate even after deleting both Pten and Socs3 genes. It may suggest that other mechanisms than mTOR or Stat3 regulate the axon regeneration in M1 ipRGCs, because they can regenerate when presented with a peripheral graft (30). Interestingly, M1 ipRGCs have intraretinal axon collaterals that terminate in the inner plexiform layer of the retina (31).…”

Section: Discussionmentioning

confidence: 99%

Promoting axon regeneration in the adult CNS by modulation of the melanopsin/GPCR signaling

Yang

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

109

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Cell-type-specific G protein-coupled receptor (GPCR) signaling regulates distinct neuronal responses to various stimuli and is essential for axon guidance and targeting during development. However, its function in axonal regeneration in the mature CNS remains elusive. We found that subtypes of intrinsically photosensitive retinal ganglion cells (ipRGCs) in mice maintained high mammalian target of rapamycin (mTOR) levels after axotomy and that the light-sensitive GPCR melanopsin mediated this sustained expression. Melanopsin overexpression in the RGCs stimulated axonal regeneration after optic nerve crush by up-regulating mTOR complex 1 (mTORC1). The extent of the regeneration was comparable to that observed after phosphatase and tensin homolog (Pten) knockdown. Both the axon regeneration and mTOR activity that were enhanced by melanopsin required light stimulation and Gq/11 signaling. Specifically, activating Gq in RGCs elevated mTOR activation and promoted axonal regeneration. Melanopsin overexpression in RGCs enhanced the amplitude and duration of their light response, and silencing them with Kir2.1 significantly suppressed the increased mTOR signaling and axon regeneration that were induced by melanopsin. Thus, our results provide a strategy to promote axon regeneration after CNS injury by modulating neuronal activity through GPCR signaling.axon regeneration | neuronal activity | melanopsin | GPCR | mTOR S evered axons in the adult mammalian CNS do not spontaneously regenerate to restore lost functions. The failure of axons to regenerate is mainly attributed to the diminished growth capacity of neurons as well as an inhibitory environment (1-6). Optic nerves have been extensively studied for mechanisms regulating axon regeneration in CNS. When presented with permissive substrates such as a sciatic nerve graft, only axons of small populations of retinal ganglion cells (RGCs) regrow into the graft (7). When the intrinsic growth program is boosted, distinct subtypes of RGCs regenerate their axons (8). These findings indicate that the differential responses of RGCs to axotomy and growth stimulation are related to their intrinsic properties. One of the critical determinants of the intrinsic regenerative abilities of adult RGCs is neuronal mammalian target of rapamycin (mTOR) activity (9). In retinal axons, the loss of the potential to regrow is accompanied by down-regulation of mTOR activity in RGCs with maturation, and further reduction after axotomy. However, a small percentage of RGCs maintain high mTOR activation levels after optic nerve crush (9, 10). One can ask whether specific subsets of RGCs differ in their ability to maintain mTOR activation. Deciphering the physiological mechanism behind the mTOR maintenance could help elucidate the differential responses of neurons to injury signals and develop strategies to promote axon regeneration.Type 1 melanopsin expressing intrinsically photosensitive retinal ganglion cells (M1 ipRGCs) and αRGCs are resistant to axotomy-induced cell death (8, 11). M1 ipRGCs mainl...

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Section: Discussionmentioning

confidence: 99%

Promoting axon regeneration in the adult CNS by modulation of the melanopsin/GPCR signaling

Yang

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

109

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“…A 1-way ANOVA with Bonferroni's correction for pairwise comparisons was used to test for differences between groups with a significance level of P < 0.05. The total number of RGCs in mice averages 50,000-60,000 (43), approximately 12% of which survive beyond a month after injury to the optic nerve (44).…”

Section: Figurementioning

confidence: 99%

Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation

Iskandar¹,

Rizk²,

Meier³

et al. 2010

J. Clin. Invest.

145

119

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The folate pathway plays a crucial role in the regeneration and repair of the adult CNS after injury. Here, we have shown in rodents that such repair occurs at least in part through DNA methylation. In animals with combined spinal cord and sciatic nerve injury, folate-mediated CNS axon regeneration was found to depend on injury-related induction of the high-affinity folate receptor 1 (Folr1). The activity of folate was dependent on its activation by the enzyme dihydrofolate reductase (Dhfr) and a functional methylation cycle. The effect of folate on the regeneration of afferent spinal neurons was biphasic and dose dependent and correlated closely over its dose range with global and gene-specific DNA methylation and with expression of both the folate receptor Folr1 and the de novo DNA methyltransferases. These data implicate an epigenetic mechanism in CNS repair. Folic acid and possibly other nontoxic dietary methyl donors may therefore be useful in clinical interventions to promote brain and spinal cord healing. If indeed the benefit of folate is mediated by epigenetic mechanisms that promote endogenous axonal regeneration, this provides possible avenues for new pharmacologic approaches to treating CNS injuries.

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“…Recently, mRGCs are shown to be less susceptible to death after complete ONT in mice (Robinson and Madison 2004). Following that, our group found that mRGCs survive relatively longer in the ocular hypertension (OH) model, whereas a significant number of superior colliculusprojecting RGCs (scRGCs) die in the process (Li et al 2006a).…”

Section: Introductionmentioning

confidence: 96%

Enhanced Survival of Melanopsin-expressing Retinal Ganglion Cells After Injury is Associated with the PI3 K/Akt Pathway

Yau

Chen

et al. 2008

Cell Mol Neurobiol

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In the present study, we studied the factors that contribute to the injury-resistant property of melanopsin-expressing retinal ganglion cells (mRGCs). Since phosphatidylinositol-3 kinase (PI3 K)/Akt signaling pathway is one of the well-known pathways for neuronal cell survival, we investigated the survival of mRGCs by applying the PI3 K/Akt specific inhibitors after injury. Two injury models, unilateral optic nerve transection and ocular hypertension, were adopted using Sprague-Dawley rats. Inhibitors of PI3 K/Akt were injected intravitreally following injuries to inhibit the PI3 K/Akt signaling pathway. Retinas were dissected after designated survival time, immunohistochemistry was carried out to visualize the mRGCs using melanopsin antibody and the number of mRGCs was counted. Co-expression of melanopsin and phospho-Akt (pAkt) was also examined. Compared to the survival of non-melanopsin-expressing RGCs, mRGCs showed a marked resistance to injury and co-expressed pAkt. Application of PI3 K/Akt inhibitors decreased the survival of mRGCs after injury. Our previous study has shown that mRGC are less susceptible to injury following the induction of ocular hypertension. In this study, we report that mRGCs were injury-resistant to a more severe type of injury, the optic nerve transection. More importantly, the PI3 K/Akt pathway was found to play a role in maintaining the survival of mRGCs after injury.

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Axotomized mouse retinal ganglion cells containing melanopsin show enhanced survival, but not enhanced axon regrowth into a peripheral nerve graft

Cited by 96 publications

References 30 publications

Promoting axon regeneration in the adult CNS by modulation of the melanopsin/GPCR signaling

Promoting axon regeneration in the adult CNS by modulation of the melanopsin/GPCR signaling

Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation

Enhanced Survival of Melanopsin-expressing Retinal Ganglion Cells After Injury is Associated with the PI3 K/Akt Pathway

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