The synergistic effects of NGF and IGF‐1 on neurite growth in adult sensory neurons: convergence on the PI 3‐kinase signaling pathway

Jones, David; Tucker, Budd A.; Rahimtula, Masuma; Mearow, Karen M.

doi:10.1046/j.1471-4159.2003.01925.x

Cited by 165 publications

(126 citation statements)

References 56 publications

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“…The essential role of the PI3K/AKT signalling pathway in stimulating axon regenerative processes in the adult central and peripheral nervous systems is well documented 8,[27][28][29][30] . Activated AKT phosphorylates GSK3a at serine 21 (pGSK3a) and GSK3b at serine 9 (pGSK3b) and thereby inhibits their respective kinase activity 7,31,32 .…”

Section: Discussionmentioning

confidence: 99%

Sustained GSK3 activity markedly facilitates nerve regeneration

et al. 2014

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Promotion of axonal growth of injured DRG neurons improves the functional recovery associated with peripheral nerve regeneration. Both isoforms of glycogen synthase kinase 3 (GSK3; a and b) are phosphorylated and inactivated via phosphatidylinositide 3-kinase (PI3K)/AKT signalling upon sciatic nerve crush (SNC). However, the role of GSK3 phosphorylation in this context is highly controversial. Here we use knock-in mice expressing GSK3 isoforms resistant to inhibitory PI3K/AKT phosphorylation, and unexpectedly find markedly accelerated axon growth of DRG neurons in culture and in vivo after SNC compared with controls. Moreover, this enhanced regeneration strikingly accelerates functional recovery after SNC. These effects are GSK3 activity dependent and associated with elevated MAP1B phosphorylation. Altogether, our data suggest that PI3K/AKT-mediated inhibitory phosphorylation of GSK3 limits the regenerative outcome after peripheral nerve injury. Therefore, suppression of this internal 'regenerative break' may potentially provide a new perspective for the clinical treatment of nerve injuries.

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Section: Discussionmentioning

confidence: 99%

Sustained GSK3 activity markedly facilitates nerve regeneration

et al. 2014

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“…IGF-I may also have an anti-apoptotic effect, as the phosphorylation of forkhead proteins, important mediators of growth factorstimulated cellular survival, also depends upon PI 3-K and Akt [35]. It is clear now that activation of Akt and MAPK also correlates with sensory neurite elongation and branching [36]. PI 3-K and Akt may be more important for sensory neurite extension and branching than MAPKdependent signalling, which may, in fact, be inhibitory to sensory neuritic branching [36], although this is controversial [37].…”

Section: Discussionmentioning

confidence: 99%

“…It is clear now that activation of Akt and MAPK also correlates with sensory neurite elongation and branching [36]. PI 3-K and Akt may be more important for sensory neurite extension and branching than MAPKdependent signalling, which may, in fact, be inhibitory to sensory neuritic branching [36], although this is controversial [37]. Elegant compartmentalised culture studies have demonstrated that IGF-1 (but neither fibroblast growth factor nor endothelial growth factor) potentiates distal neurite growth into side compartments only when IGF-1 is applied to cell bodies [37].…”

Section: Discussionmentioning

confidence: 99%

Remote neurotrophic support of epidermal nerve fibres in experimental diabetes

2006

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Aims/hypothesis: The support of distal regenerating axons and epidermal nerve fibres through growth factor delivery may depend on the site of delivery. While low-dose systemic insulin provides trophic support for regenerating axons or axons from diabetic animals, its potential action upon the most distal neurites within the epidermis is unknown. In diabetic neuropathy, distal loss of axons is an important clinical and pathological feature. We hypothesised that insulin and IGF-1 delivered intrathecally could support the most distal epidermal nerve fibres. Materials and methods: As insulin and IGF-1 receptors are present upon sensory ganglion perikarya, we studied the impact of intrathecal delivery of low-dose insulin and equimolar IGF-1 on the density of epidermal axons expressing protein gene product 9.5 in experimental diabetic rats. After 2 months of diabetes induced by streptozotocin injection, intrathecal delivery of low-dose insulin or IGF-1 or saline was provided for 1 month, with comparison to compatible doses of subcutaneous insulin delivery. Results: Diabetes, in itself, was associated with a decline in epidermal nerve fibre density. Delivery of both intrathecal IGF-1 and insulin was associated with significant improvement in epidermal fibre density (greatest with IGF-1) and length relative to placebo. Conclusions/ interpretation: Central intrathecal delivery of IGF-1 and insulin offers remote support for epidermal nerve fibres, subjected to 'dying-back' in early diabetic polyneuropathy.

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“…One approach involves exogenous application of growth factors, such as nerve growth factor (NGF) (Jones et al, 2003;Kemp et al, 2007). Another uses knock-out of PTEN; however, the loss of PTEN is oncogenic and a long-term knock-out in particular tissues might lead to neoplasia (Ali et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

PTEN Inhibition to Facilitate Intrinsic Regenerative Outgrowth of Adult Peripheral Axons

Christie¹,

Webber²,

Martinez³

et al. 2010

Journal of Neuroscience

305

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 synergistic effects of NGF and IGF‐1 on neurite growth in adult sensory neurons: convergence on the PI 3‐kinase signaling pathway

Cited by 165 publications

References 56 publications

Sustained GSK3 activity markedly facilitates nerve regeneration

Sustained GSK3 activity markedly facilitates nerve regeneration

Remote neurotrophic support of epidermal nerve fibres in experimental diabetes

PTEN Inhibition to Facilitate Intrinsic Regenerative Outgrowth of Adult Peripheral Axons

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