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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    • "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). "
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    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
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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.
    Full-text · Article · Nov 2015 · Neuron
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    • "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. "
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