PTEN Deletion Enhances the Regenerative Ability of Adult Corticospinal Neurons

F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.
Nature Neuroscience (Impact Factor: 16.1). 09/2010; 13(9):1075-81. DOI: 10.1038/nn.2603
Source: PubMed


Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. We found that PTEN/mTOR are critical for controlling the regenerative capacity of mouse corticospinal neurons. After development, the regrowth potential of CST axons was lost and this was accompanied by a downregulation of mTOR activity in corticospinal neurons. Axonal injury further diminished neuronal mTOR activity in these neurons. Forced upregulation of mTOR activity in corticospinal neurons by conditional deletion of Pten, a negative regulator of mTOR, enhanced compensatory sprouting of uninjured CST axons and enabled successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possessed the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.

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Available from: Oswald Steward, Oct 02, 2015
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    • "The effects in DRGs were limited to a reduction in net axonal retraction, but effects in CST neurons were more pronounced. Indeed, although comparisons between experiments must be made cautiously, the magnitude of the CST response, when normalized to the total number of transduced CST axons, appears to be similar to that reported previously for PTEN (phosphatase and tensin homolog) knockout and overexpression of VP16-KLF7 (Liu et al., 2010; Blackmore et al., 2012). AAV8-driven protein expression commences within a week of injection (Blackmore et al., 2012), so in the first CST regeneration experiment exogenous Sox11 protein was likely already present at the time of injury. "
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    ABSTRACT: Embryonic neurons, peripheral neurons, and CNS neurons in zebrafish respond to axon injury by initiating pro-regenerative transcriptional programs that enable axons to extend, locate appropriate targets, and ultimately contribute to behavioral recovery. In contrast, many long-distance projection neurons in the adult mammalian CNS, notably corticospinal tract (CST) neurons, display a much lower regenerative capacity. To promote CNS repair, a long-standing goal has been to activate pro-regenerative mechanisms that are normally missing from injured CNS neurons. Sox11 is a transcription factor whose expression is common to a many types of regenerating neurons, but it is unknown whether suboptimal Sox11 expression contributes to low regenerative capacity in the adult mammalian CNS. Here we show in adult mice that dorsal root ganglion neurons (DRGs) and CST neurons fail to upregulate Sox11 after spinal axon injury. Furthermore, forced viral expression of Sox11 reduces axonal dieback of DRG axons, and promotes CST sprouting and regenerative axon growth in both acute and chronic injury paradigms. In tests of forelimb dexterity, however, Sox11 overexpression in the cortex caused a modest but consistent behavioral impairment. These data identify Sox11 as a key transcription factor that can confer an elevated innate regenerative capacity to CNS neurons. The results also demonstrate an unexpected dissociation between axon growth and behavioral outcome, highlighting the need for additional strategies to optimize the functional output of stimulated neurons. Copyright © 2015 the authors 0270-6474/15/353139-07$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2015; 35(7):3139-45. DOI:10.1523/JNEUROSCI.2832-14.2015 · 6.34 Impact Factor
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    • "However, PTEN deletion does not seem to facilitate intrinsic regenerative outgrowth of adult peripheral axons (Christie et al., 2010). Rather, it enhances regeneration of axons after CNS injury (Park et al., 2008) and in adult cortico-spinal neurons after spinal cord injury (Liu et al., 2010). These studies highlight the importance of the role of PTEN in neuronal development and possibly axon outgrowth. "
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    ABSTRACT: PTEN serves as an intrinsic brake on neurite outgrowth, but the regulatory mechanism that governs its action is not clear. In the present study, miR-29a was found to increase neurite outgrowth by decreasing PTEN expression. Results showed that miR-92a-1, miR-29a, miR-92b, and miR-29c expression levels increased during nerve growth factor (NGF)-induced differentiation of PC12 cells. Based on in silico analysis of possible miR-29a targets, PTEN mRNA may be a binding site for miR-29a. A protein expression assay and luciferase reporter assay showed that miR-29a could directly target the 3'-UTR (untranslated regions) of PTEN mRNA and down-regulate the expression of PTEN. PC12 cells infected with lentiviral pLKO-miR-29a showed far higher levels of miR-29a and Akt phosphorylation level than those infected with control. This promoted neurite outgrowth of PC12 cells. Collectively, these results indicate that miR-29a is an important regulator of neurite outgrowth via targeting PTEN and that it may be a promising therapeutic target for neural disease. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
    Neuroscience 02/2015; 291. DOI:10.1016/j.neuroscience.2015.01.055 · 3.36 Impact Factor
    • "Upregulation of cAMP through the pharmacological agonist Rolipram increases the inherent plastic potential of sensory and motor tracts, potentially through PKA or MAPK-ERK activation (Pearse et al., 2004b). Inhibition of PTEN/mTOR pathway has been utilized to elicit remarkable regenerative capacity in major motor tracts following sharp and contusive SCI models (Park et al., 2008; Liu et al., 2010). Neural repair through reconnection may also be possible through activating endogenous programs and resident stem cells; however, currently the most successful strategies have combined stem cell transplantation with a synergistic activator of neuroplasticity. "
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    ABSTRACT: Stem cell transplantation offers an attractive potential therapy for neurological and neurodegenerative disorders such as spinal cord injury (SCI). Given the demand and expectations for the success of regenerative medicines, newly developed cellular therapeutics must be carefully designed and executed, informed by strong preclinical rationale available. This chapter will address the current state of preclinical scientific research for translation into clinical use of stem cell therapy. Focus will be given to current advances in cell transplantation strategies, with specific attention paid to critical assessment of mechanism and efficacy. Specific cell types will be discussed with respect to pathophysiological processes of SCI and their proposed targets. These therapeutics targets include: 1) trophic support and reducing cell loss, 2) remyelination and neuroprotection, 3) tissue modification, and 4) regeneration through neuroplasticity. Combinatorial strategies consisting of co-administering cell types, neurotrophins and tissue modification will also be addressed. Pressing considerations and challenges of translating preclinical findings into clinical therapy exist, and ought to be critically assessed with respect to the best current animal model data. Clinical trials of cell transplantation in human participants with spinal injuries are of significant importance, and will be critically appraised. Taken as a whole—while expectations must be measured—the current status of knowledge on stem cell transplantation for SCI has evolved substantially over the past decade. While translational knowledge gaps continue to exist with regard to cervical and chronic SCI, carefully conducted early phase clinical trials with cellular therapies are warranted, but must be complemented by a robust preclinical research strategy.
    Stem Cells and Neurological Disorders, Edited by L Lescaundron, 01/2015: chapter 3: pages 61-92; Science Publishers.
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