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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    • "Effects of PTEN Deletion We reasoned that the direct effects of DCLK2 overexpression might be mainly limited to the axon cytoskeleton, and it might have functional interactions with other identified regeneration regulators. As our previous studies indicated that manipulating the mTOR pathway could enhance neuronal regeneration (Liu et al., 2010; Park et al., 2008; Sun et al., 2011; Zukor et al., 2013), we tested the combinatorial outcomes of DCLK2 overexpression and PTEN deletion. PTEN f/f mice received successive intravitreal injections of AAV2-Cre and AAV2-DCLK2 or control (AAV2-PLAP) viruses (Figures 2A–2C). "
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    ABSTRACT: After axotomy, neuronal survival and growth cone re-formation are required for axon regeneration. We discovered that doublecortin-like kinases (DCLKs), members of the doublecortin (DCX) family expressed in adult retinal ganglion cells (RGCs), play critical roles in both processes, through distinct mechanisms. Overexpression of DCLK2 accelerated growth cone re-formation in vitro and enhanced the initiation and elongation of axon re-growth after optic nerve injury. These effects depended on both the microtubule (MT)-binding domain and the serine-proline-rich (S/P-rich) region of DCXs in-cis in the same molecules. While the MT-binding domain is known to stabilize MT structures, we show that the S/P-rich region prevents F-actin destabilization in injured axon stumps. Additionally, while DCXs synergize with mTOR to stimulate axon regeneration, alone they can promote neuronal survival possibly by regulating the retrograde propagation of injury signals. Multifunctional DCXs thus represent potential targets for promoting both survival and regeneration of injured neurons.
    Neuron 11/2015; 88(4). DOI:10.1016/j.neuron.2015.10.005 · 15.05 Impact Factor
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    • "This supports the notion that successful CNS regeneration is limited by more than just the inhospitable environment presented by scar tissue in the injured spinal cord. Deletion of negative regulators of mammalian target of rapamycin (mTOR) such as phosphatase and tensin homolog (PTEN) or tuberous sclerosis protein 1 (TSC1) facilitates remarkable improvement in regeneration of optic nerve and corticospinal tract axons (Liu et al., 2010; Park et al., 2008). These studies highlight the potential for boosting the intrinsic regenerative potential of injured CNS neurons. "
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    ABSTRACT: Insufficient regeneration of central nervous system (CNS) axons contributes to persisting neurological dysfunction after spinal cord injury (SCI). Peripheral nerve grafts (PNGs) support regeneration by thousands of injured intraspinal axons and help them bypass some of the extracellular barriers that form after SCI. However this number represents but a small portion of the total number of axons that are injured. Here we tested if rhythmic sensory stimulation during cycling exercise would boost the intrinsic regenerative state of neurons to enhance axon regeneration into PNGs after a lower thoracic (T12) spinal transection of adult rats. Using True Blue retrograde tracing, we show that 4weeks of cycling improves regeneration into a PNG from lumbar interneurons but not by primary sensory neurons. The majority of neurons that regenerate their axon are within 5mm of the lesion and their number increased 70% with exercise. Importantly propriospinal neurons in more distant regions (5-20mm from the lesion) that routinely exhibit very limited regeneration responded to exercise by increasing the number of regenerating neurons by 900%. There was no exercise-associated increase in regeneration from sensory neurons. Analyses using fluorescent in situ hybridization showed that this increase in regenerative response is associated with changes in levels of mRNAs encoding the regeneration associated genes (RAGs) GAP43, β-actin and Neuritin. While propriospinal neurons showed increased mRNA levels in response to SCI alone and then to grafting and exercise, sensory neurons did not respond to SCI, but there was a response to the presence of a PNG. Thus, exercise is a non-invasive approach to modulate gene expression in injured neurons leading to an increase in regeneration. This sets the stage for future studies to test whether exercise will promote axon outgrowth beyond the PNG and reconnection with spinal cord neurons, thereby demonstrating a potential clinical application of this combined therapeutic intervention.
    Experimental Neurology 09/2015; DOI:10.1016/j.expneurol.2015.09.004 · 4.70 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
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