Mammalian Target of Rapamycin (mTOR) Activation Increases Axonal Growth Capacity of Injured Peripheral Nerves

Abe, Namiko; Borson, Steven; Gambello, Michael J.; Wang, Fan; Cavalli, Valeria

doi:10.1074/jbc.m110.125336

Cited by 193 publications

(214 citation statements)

References 58 publications

(71 reference statements)

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“…PI3K/Akt/mTOR signaling has been shown to promote growth and branching in hippocampal neurons [16] . In recent reports, mTOR promoted axonal regeneration in the adult central nervous system and increased the axonal growth of injured peripheral nerves [36,37] . In our experiment, atorvastatin increased the activation of mTOR and p70S6K while rapamycin, an inhibitor of mTOR, decreased the effect of atorvastatin on neurite outgrowth.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin enhances neurite outgrowth in cortical neurons in vitro via up-regulating the Akt/mTOR and Akt/GSK-3β signaling pathways

et al. 2012

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Aim: To investigate whether atorvastatin can promote formation of neurites in cultured cortical neurons and the signaling mechanisms responsible for this effect. Methods: Cultured rat cerebral cortical neurons were incubated with atorvastatin (0.05-10 μmol/L) for various lengths of time. For pharmacological experiments, inhibitors were added 30 min prior to addition of atorvastatin. Control cultures received a similar amount of DMSO. Following the treatment period, phase-contrast digital images were taken. Digital images of neurons were analyzed for total neurite branch length (TNBL), neurite number, terminal branch number, and soma area by SPOT Advanced Imaging software. After incubation with atorvastatin for 48 h, the levels of phosphorylated 3-phosphoinoside-dependent protein kinase-1 (PDK1), phospho-Akt, phosphorylated mammalian target of rapamycin (mTOR), phosphorylated 4E-binding protein 1 (4E-BP1), p70S6 kinase (p70S6K), and glycogen synthase kinase-3β (GSK-3β) in the cortical neurons were evaluated using Western blotting analyses. Results: Atorvastatin (0.05-10 µmol/L) resulted in dose-dependent increase in neurite number and length in these neurons. Pretreatment of the cortical neurons with phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 (30 µmol/L) and wortmannin (5 µmol/L), Akt inhibitor tricribine (1 µmol/L) or mTOR inhibitor rapamycin (100 nmol/L) blocked the atorvastatin-induced increase in neurite outgrowth, suggesting that atorvastatin promoted neurite outgrowth via activating the PI3K/Akt/mTOR signaling pathway. Atorvastatin (10 µmol/L) significantly increased the levels of phosphorylated PDK1, Akt and mTOR in the cortical neurons, which were prevented by LY294002 (30 µmol/L). Moreover, atorvastatin (10 µmol/L) stimulated the phosphorylation of 4E-BP1 and p70S6K, the substrates of mTOR, in the cortical neurons. In addition, atorvastatin (10 µmol/L) significantly increased the phosphorylated GSK-3β level in the cortical neurons, which was prevented by both LY294002 and tricribine. Conclusion: These results suggest that activation of both the PI3K/Akt/mTOR and Akt/GSK-3β signaling pathways is responsible for the atorvastatin-induced neurite outgrowth in cultured cortical neurons.

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Section: Discussionmentioning

confidence: 99%

Atorvastatin enhances neurite outgrowth in cortical neurons in vitro via up-regulating the Akt/mTOR and Akt/GSK-3β signaling pathways

et al. 2012

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“…Several signaling molecules have been reported to be both regulated by PP1 and involved in the regulation of neurite growth (Abe et al, 2010;Bito et al, 1996;Gao et al, 2004;Hur et al, 2011;Morfini et al, 2004;Shi et al, 2004;Stegmüller et al, 2008;Thayyullathil et al, 2011;Xiao et al, 2010;Zhou et al, 2004). Dephosphorylation of Akt/glycogen synthase kinase 3 beta (GSK3b), cAMP-response element binding protein (CREB) and TbRI by PP1 regulates the phosphatidylinositol 3-kinase (PI3K), cAMP/PKA and TGF-b/Smad signaling pathways, respectively.…”

Section: Ipp5 Maintains Tgf-b Signalingmentioning

confidence: 99%

IPP5 inhibits neurite growth in primary sensory neurons by maintaining TGF- /Smad signaling

Han

Gao

Guo-QiangMa

et al. 2012

Journal of Cell Science

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SummaryDuring nerve regeneration, neurite growth is regulated by both intrinsic molecules and extracellular factors. Here, we found that inhibitor 5 of protein phosphatase 1 (IPP5), a newly identified inhibitory subunit of protein phosphatase 1 (PP1), inhibited neurite growth in primary sensory neurons as an intrinsic regulator. IPP5 was highly expressed in the primary sensory neurons of rat dorsal root ganglion (DRG) and was downregulated after sciatic nerve axotomy. Knocking down IPP5 with specific shRNA increased the length of the longest neurite, the total neurite length and the number of neurite ends in cultured rat DRG neurons. Mutation of the PP1-docking motif K 8 IQF 11 or the PP1-inhibiting motif at Thr 34 eliminated the IPP5-induced inhibition of neurite growth. Furthermore, biochemical experiments showed that IPP5 interacted with type I transforming growth factor-b receptor (TbRI) and PP1 and enhanced transforming growth factor-b (TGF-b)/Smad signaling in a PP1-dependent manner. Overexpressing IPP5 in DRG neurons aggravated TGF-b-induced inhibition of neurite growth, which was abolished by blocking PP1 or IPP5 binding to PP1. Blockage of TGF-b signaling with the TbRI inhibitor SB431542 or Smad2 shRNA attenuated the IPP5-induced inhibition of neurite growth. Thus, these data indicate that selectively expressed IPP5 inhibits neurite growth by maintaining TGF-b signaling in primary sensory neurons.

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“…The level of mTOR activity in CNS neurons declines during development (Park et al, 2008), correlating with the decrease in their regrowth ability. We and others have demonstrated that deletion of phosphatase and tensin homolog (PTEN) or tuberous sclerosis proteins 1/2 in several different types of CNS neurons enhances axonal regeneration, an effect inhibited by mTOR blockade (Park et al, 2008;Abe et al, 2010;Byrne et al, 2014). In contrast, others have reported minimal roles of mTOR in promoting axon regeneration in sensory neurons (Christie et al, 2010), indicating that neurons under different conditions may employ mTOR-dependent or independent mechanisms to trigger axonal regrowth.…”

Section: Introductionmentioning

confidence: 99%

Mammalian Target of Rapamycin's Distinct Roles and Effectiveness in Promoting Compensatory Axonal Sprouting in the Injured CNS

et al. 2014

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Mammalian target of rapamycin (mTOR) functions as a master sensor of nutrients and energy, and controls protein translation and cell growth. Deletion of phosphatase and tensin homolog (PTEN) in adult CNS neurons promotes regeneration of injured axons in an mTOR-dependent manner. However, others have demonstrated mTOR-independent axon regeneration in different cell types, raising the question of how broadly mTOR regulates axonal regrowth across different systems. Here we define the role of mTOR in promoting collateral sprouting of spared axons, a key axonal remodeling mechanism by which functions are recovered after CNS injury. Using pharmacological inhibition, we demonstrate that mTOR is dispensable for the robust spontaneous sprouting of corticospinal tract axons seen after pyramidotomy in postnatal mice. In contrast, moderate spontaneous axonal sprouting and induced-sprouting seen under different conditions in young adult mice (i.e., PTEN deletion or degradation of chondroitin proteoglycans; CSPGs) are both reduced upon mTOR inhibition. In addition, to further determine the potency of mTOR in promoting sprouting responses, we coinactivate PTEN and CSPGs, and demonstrate that this combination leads to an additive increase in axonal sprouting compared with single treatments. Our findings reveal a developmental switch in mTOR dependency for inducing axonal sprouting, and indicate that PTEN deletion in adult neurons neither recapitulates the regrowth program of postnatal animals, nor is sufficient to completely overcome an inhibitory environment. Accordingly, exploiting mTOR levels by targeting PTEN combined with CSPG degradation represents a promising strategy to promote extensive axonal plasticity in adult mammals.

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Mammalian Target of Rapamycin (mTOR) Activation Increases Axonal Growth Capacity of Injured Peripheral Nerves

Cited by 193 publications

References 58 publications

Atorvastatin enhances neurite outgrowth in cortical neurons in vitro via up-regulating the Akt/mTOR and Akt/GSK-3β signaling pathways

Atorvastatin enhances neurite outgrowth in cortical neurons in vitro via up-regulating the Akt/mTOR and Akt/GSK-3β signaling pathways

IPP5 inhibits neurite growth in primary sensory neurons by maintaining TGF- /Smad signaling

Mammalian Target of Rapamycin's Distinct Roles and Effectiveness in Promoting Compensatory Axonal Sprouting in the Injured CNS

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