PTEN couples Sema3A signalling to growth cone collapse

Chadborn, Neil; Ahmed, Aminul I.; Holt, Mark R.; Prinjha, Rabinder; Dunn, Graham; Jones, Gareth E.; Eickholt, Britta J.

doi:10.1242/jcs.02801

Cited by 125 publications

(130 citation statements)

References 37 publications

(41 reference statements)

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“…In support of this concept, we observed concurrent reductions in pAkt and pGSK3␤ expression within the injury milieu where PTEN was also expressed. Decreased phosphorylation of these molecules leads to growth cone collapse and a less supportive microenvironment at the nerve trunk injury site (Eickholt et al, 2002; Jones Chadborn et al, 2006). Our data have confirmed an active role of PTEN through pharmacological and knockdown approaches in adult peripheral neurons.…”

Section: Discussionsupporting

confidence: 67%

“…Two major downstream targets of PI3-K signaling, Akt and GSK3␤, which have been shown to be influenced by PTEN (Chadborn et al, 2006), were also identified in sensory neurons and axons (Fig. 4).…”

Section: Resultsmentioning

confidence: 95%

“…The tissue was permeabilized for 1 h in 5% goat serum, 1% BSA, and 0.3% Triton-X. The slides were probed for PTEN, pPTEN (Ser 380), Akt, or pAkt (Ser 473) (1:100) (Cell Signaling Technology) (Chadborn et al, 2006;Rankin et al, 2008), and double labeled with NF-200 (1:400) (Sigma-Aldrich), substance P (1:500, Abcam), calcitonin gene-related peptide (CGRP, 1:200, Abcam), or unconjugated IB4 lectin (Vector Laboratories) followed by goat anti-IB4 (1:8000, Vector Laboratories) for 48 h and then rinsed three times in PBS. Secondary antibodies were sheep anti-mouse IgG CY3 conjugate (1:100, Sigma) and Alexa Fluor 488 goat anti-rabbit IgG (HϩL) conjugate (1: 500, Cedarlane).…”

Section: Animals and Preconditioning Lesion Experiments Adult Male Smentioning

confidence: 99%

“…By acting as the phosphatase that converts PIP(3) (phosphatidylinositol 3,4,5 triphosphate) to PIP(2) (phosphatidylinositol 4,5 diphosphate), PTEN acts to attenuate PIP(3) activation of Akt. One action of PTEN in the unphosphorylated state and at the lipid membranes is to dampen regenerative activity in conjunction with other inhibitory molecules, such as Semaphorin 3A (Sema3A) and GSK3␤ (Chadborn et al, 2006). Recent work has also suggested that PTEN attenuates regrowth of injured CNS axons by suppression of mTOR (Park et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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PTEN Inhibition to Facilitate Intrinsic Regenerative Outgrowth of Adult Peripheral Axons

Christie¹,

Webber²,

Martinez³

et al. 2010

Journal of Neuroscience

303

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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Section: Discussionsupporting

confidence: 67%

Section: Resultsmentioning

confidence: 95%

Section: Animals and Preconditioning Lesion Experiments Adult Male Smentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

PTEN Inhibition to Facilitate Intrinsic Regenerative Outgrowth of Adult Peripheral Axons

Christie¹,

Webber²,

Martinez³

et al. 2010

Journal of Neuroscience

303

283

View full text Add to dashboard Cite

show abstract

“…Axonal growth is channeled through tissues during development without disrupting them, while invasion of tissue by cancer cells is disruptive and may result in the death of the host. The semaphorin Sema3A inhibits neurite outgrowth by inhibiting the phosphorylation of Akt (Chadborn et al, 2006). We have found that the protein kinase inhibitor staurosporine is lethal for N1E-115 cells when applied to undifferentiated cells (C.M.…”

Section: Neuroblastoma-derived Cell Linesmentioning

confidence: 99%

The Cell Biology of Neuroblastoma

Denny¹

2012

Neuroblastoma - Present and Future

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Cytoskeleton in Axon Growth

Letourneau

2016

Encyclopedia of Life Sciences

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Axons and dendrites are the neuronal processes that transmit nerve signals throughout the body. These processes are formed and maintained by the neuronal cytoskeleton, particularly microtubules and actin filaments. Microtubules are the supportive framework of neurites, axons and dendrites, as well as the rails for transporting organelles and cytoplasmic components. Actin filaments support the neuron's outer cortex, and the dynamic protrusion of actin‐filled filopodia and lamellipodia drives neuronal morphogenesis, including axon guidance, branching and regeneration. The initiation of axon formation requires advance of microtubules into filopodial protrusions adherent to the substratum. Polymerisation of microtubule plus ends and dynein‐driven transport of short microtubules provides ‘push’ for continued axonal growth. Actin‐filled protrusions at the axonal terminal, the growth cone, explore the environment for cues that bind receptors and trigger either protrusion and microtubule advance or cessation of protrusion and myosin II contractility that retracts protrusions and limits microtubule advance. Key Concepts The neuronal cytoskeleton generates and supports neuronal shape. Axonal elongation involves accumulation of microtubules through polymerisation, stabilisation and transport. The motile growth cone at the tip of an elongating axon is where the axon is steered to its synaptic target. Dynamic actin filaments drive the growth cone's exploration of its environment. Growth cone adhesive interactions allow traction that advances the growth cone. Neuronal polarisation involves regulation of cytoskeletal dynamics. Extrinsic guidance cues locally regulate actin dynamics and microtubule advance to steer the growth cone. Axonal branching involves cytoskeletal dynamics to produce new streams of microtubule advance. Success in axonal regeneration will require recapitulation of the cytoskeletal dynamics of developing neurons.

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PTEN couples Sema3A signalling to growth cone collapse

Cited by 125 publications

References 37 publications

PTEN Inhibition to Facilitate Intrinsic Regenerative Outgrowth of Adult Peripheral Axons

PTEN Inhibition to Facilitate Intrinsic Regenerative Outgrowth of Adult Peripheral Axons

The Cell Biology of Neuroblastoma

Cytoskeleton in Axon Growth

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