Article

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: 14.98). 09/2010; 13(9):1075-81. DOI: 10.1038/nn.2603
Source: PubMed

ABSTRACT 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, Aug 17, 2015
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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 · 3.33 Impact Factor
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    • "There are very promising strategies for reconnecting the brain and spinal cord after SCI, but we are far from achieving that goal. Particularly intriguing are recent genetic approaches to reprogram damaged neurons to facilitate axonal outgrowth (Liu et al., 2010); and in particular, to regenerate lost axons. Such manipulations to augment axonal outgrowth, combined with viral delivery methods that achieve cell-specificity, could be very effective. "
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    ABSTRACT: The corticospinal system-with its direct spinal pathway, the corticospinal tract (CST) - is the primary system for controlling voluntary movement. Our approach to CST repair after injury in mature animals was informed by our finding that activity drives establishment of connections with spinal cord circuits during postnatal development. After incomplete injury in maturity, spared CST circuits sprout, and partially restore lost function. Our approach harnesses activity to augment this injury-dependent CST sprouting and to promote function. Lesion of the medullary pyramid unilaterally eliminates all CST axons from one hemisphere and allows examination of CST sprouting from the unaffected hemisphere. We discovered that 10 days of electrical stimulation of either the spared CST or motor cortex induces CST axon sprouting that partially reconstructs the lost CST. Stimulation also leads to sprouting of the cortical projection to the magnocellular red nucleus, where the rubrospinal tract originates. Coordinated outgrowth of the CST and cortical projections to the red nucleus could support partial re-establishment of motor systems connections to the denervated spinal motor circuits. Stimulation restores skilled motor function in our animal model. Lesioned animals have a persistent forelimb deficit contralateral to pyramidotomy in the horizontal ladder task. Rats that received motor cortex stimulation either after acute or chronic injury showed a significant functional improvement that brought error rate to pre-lesion control levels. Reversible inactivation of the stimulated motor cortex reinstated the impairment demonstrating the importance of the stimulated system to recovery. Motor cortex electrical stimulation is an effective approach to promote spouting of spared CST axons. By optimizing activity-dependent sprouting in animals, we could have an approach that can be translated to the human for evaluation with minimal delay.
    Frontiers in Integrative Neuroscience 06/2014; 8:51. DOI:10.3389/fnint.2014.00051
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    • "Since only the intact axons are labeled, this is a model to study purely axonal sprouting rather than bona fide regeneration. The completeness of the lesion can be verified by PKCγ immunohistochemistry of spinal crosssections , which show much more robust immunostaining in the intact main CST [41] [42] [44] [45] . one unique feature of the pyramidotomy model is the absence of a significant glial scar, which is typically observed after SCi. "
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    ABSTRACT: With advances in genetic and imaging techniques, investigating axon regeneration after spinal cord injury in vivo is becoming more common in the literature. However, there are many issues to consider when using animal models of axon regeneration, including species, strains and injury models. No single particular model suits all types of experiments and each hypothesis being tested requires careful selection of the appropriate animal model. in this review, we describe several commonly-used animal models of axon regeneration in the spinal cord and discuss their advantages and disadvantages.
    Neuroscience Bulletin 08/2013; 29(4):436-44. DOI:10.1007/s12264-013-1365-4 · 1.83 Impact Factor
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