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: 16.1). 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.

Download full-text

Full-text

Available from: Oswald Steward
  • Source
    • "For example, neutralization or removal of growth inhibitory activities has been shown to enhance the regrowth of limited types of CNS axons with significant functional outcomes (Yiu and He, 2006;Lee and Zheng, 2008;Chew et al., 2012;Cregg et al., 2014;Schwab and Strittmatter, 2014;Silver et al., 2015). In addition, regeneration can be enhanced by manipulating regulators of signaling pathways related to neuronal growth, such as PTEN/mTOR and SOCS3/ STAT3 (Park et al., 2008;Smith et al., 2009;Liu et al., 2010;Belin et al., 2015), as well as development-associated transcription factors such as Krü ppel-like family of transcription factors (Moore et al., 2009;Blackmore et al., 2012). For example, we found that genetic deletion of both PTEN and SOCS3 greatly invigorates the intrinsic regenerative ability of injured retinal ganglion cells (RGCs), resulting in robust long-distance axon regeneration in an intraorbital optic nerve injury model (Sun et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although a number of repair strategies have been shown to promote axon outgrowth following neuronal injury in the mammalian CNS, it remains unclear whether regenerated axons establish functional synapses and support behavior. Here, in both juvenile and adult mice, we show that either PTEN and SOCS3 co-deletion, or co-overexpression of osteopontin (OPN)/insulin-like growth factor 1 (IGF1)/ciliary neurotrophic factor (CNTF), induces regrowth of retinal axons and formation of functional synapses in the superior colliculus (SC) but not significant recovery of visual function. Further analyses suggest that regenerated axons fail to conduct action potentials from the eye to the SC due to lack of myelination. Consistent with this idea, administration of voltage-gated potassium channel blockers restores conduction and results in increased visual acuity. Thus, enhancing both regeneration and conduction effectively improves function after retinal axon injury.
    Full-text · Article · Jan 2016 · Cell
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Nov 2015 · Neuron
  • Source
    • "Furthermore, previous reports have demonstrated that mTOR activation promotes axon regeneration in vivo (Park et al., 2008; Smith et al., 2009; Liu et al., 2010; Sun et al., 2011). The activation of mTOR signalling results in phosphorylation of ribosomal protein S6 (p-S6); this phosphorylation of S6 has been correlated positively with axon regeneration in the mature CNS (Park et al., 2008; Smith et al., 2009; Liu et al., 2010; Sun et al., 2011). It is reported here that unilateral injections of ET-1 in the mouse brain result in skilled motor impairment and forelimb asymmetry. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Clinical stroke usually results from a cerebral ischemic event and is frequently a debilitating condition with limited treatment options. A significant proportion of clinical strokes result from specific damage to the subcortical white matter (SWM), but currently there are few animal models available to investigate the pathogenesis and potential therapeutic strategies to promote recovery. Granulocyte macrophage colony stimulating factor (GM-CSF) is a cytokine that has been previously shown to promote neuroprotective effects after brain damage, however the mechanisms mediating this effect are not known. Here, we report that GM-CSF treatment results in dramatic functional improvement in a white matter model of stroke in mice. We induced SWM stroke in mice by unilateral injections of the vasoconstrictor, endothelin-1 (ET-1). Our results reveal that ET-1-induced stroke impairs skilled motor function on the single pellet-reaching task and results in forelimb asymmetry, in adult mice. Treatment with GM-CSF, after stroke, restores motor function and abolishes forelimb asymmetry. Our results also indicate that GM-CSF promotes its effects by activating mammalian target of rapamycin (mTOR) signaling mechanisms in the brain following stroke injury. Additionally, we found a significant increase in GM-CSF receptor expression in the ipsilateral hemisphere of the ET-1-injected brain. Taken together, the present study highlights the use of an under-utilized mouse model of stroke (using ET-1) and suggests that GM-CSF treatment can attenuate ET-1-induced functional deficits. This article is protected by copyright. All rights reserved.
    Full-text · Article · Oct 2015 · European Journal of Neuroscience
Show more